No retraction, correction or concern found when last checked on Oct 19, 2026.

The Therapeutic Potential of Metformin in Neurodegenerative Diseases

Carola Rotermund, Gerrit Machetanz, Julia C. Fitzgerald

Frontiers in Endocrinology · 2018 · Review

doi:10.3389/fendo.2018.00400 (opens in a new tab)

Abstract

The search for treatments for neurodegenerative diseases is a major concern in light of today’s aging population and an increasing burden on individuals, families and society. Although great advances have been made in the last decades to understand the underlying genetic and biological cause of these diseases, only some symptomatic treatments are available. Metformin has long since been used to treat Type 2 Diabetes and has been shown to be beneficial in several other conditions. Metformin is well-tested in vitro and an approved compound that targets diverse pathways including mitochondrial energy production and insulin signaling. There is growing evidence for the benefits of metformin to counteract age-related diseases such as cancer, cardiovascular disease and neurodegenerative diseases. We will discuss evidence showing that certain neurodegenerative diseases and diabetes are explicitly linked and that metformin along with other diabetes drugs can reduce neurological symptoms in some patients and reduce disease phenotypes in animal and cell models. An interesting therapeutic factor might be how metformin is able to balance survival and death signaling in cells through pathways that are commonly associated with neurodegenerative diseases. In healthy neurons, these overarching signals keep energy metabolism, oxidative stress and proteostasis in check, avoiding the dysfunction and neuronal death that defines neurodegenerative disease. We will discuss the biological mechanisms involved and the relevance of neuronal vulnerability and potential difficulties for future trials and development of therapies.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1The evolution of genomics has greatly advanced our understanding of the genetic contribution to neurodegenerative diseases and provided an entry point for studying the biological cascades leading to neuronal degeneration. The growing research areas of bioinformatics and systems medicine have also opened up opportunities for better targeted treatments and individualized therapies. However, even for diseases such as Alzheimer's and Parkinson's disease, in which much progress has been made, a clear link between genetics, underlying pathological processes and the resulting clinical phenotype seldom exists. Neurodegenerative diseases are currently incurable, debilitating conditions caused by the progressive degeneration and death of nerve cells and their prevalence is rising in today's society.

2Therefore, despite substantial advances in the development of symptomatic treatments for Alzheimer's disease (AD) and Parkinson's disease (PD) (Figure 1), there is still a major need for novel therapeutic strategies and disease-modifying treatments.

3Given the complex and heterogeneous molecular basis of neurodegenerative disease the task can appear overwhelming and the previous decades have seen mostly disappointing clinical trial outcomes and subsequent lack of financial investment.

4Gallega officinalis (French lilac) contains glucose-lowering guanidines and has been used for treatment of diabetes for centuries. The derivate metformin is a biguanide which was introduced in Europe in the 1950s and in the United States in the 1990s. Metformin has recently been reported to decrease cardiovascular risk, restore ovarian function in polycystic ovary syndrome, reduce hepatic lipogenesis, fatty liver disease, and reduce oxidative stress. The mechanisms by which metformin exerts its effects are still not fully defined but it is known that metformin inhibits glucose production in the liver and increases glucose uptake in peripheral tissues thereby lowering blood glucose levels. It is also accepted that metformin slows mitochondrial respiration via its direct action on complex I of the respiratory chain of mitochondria.

The therapeutic potential of metformin: rationale

5Metformin has the potential to interfere with neuronal longevity mechanisms and is therefore an interesting drug since it has already been approved for human use. However, human aging research in general has been slowed down by the lack of good aging models that can be used in the laboratory. Retaining aging signatures in reprogrammed neurons has been made possible by the use of direct reprogramming protocols but this may not be feasible for some research groups and time is needed for the technologies to be established in non-expert laboratories. New, simple and affordable methods to investigate the role of aging in human cells are still greatly needed.

6Nonetheless, data from human and animal studies regardless of cell type have shown that dysregulation of insulin function contributes to aging and the development of neurodegenerative diseases. Insulin resistance and diabetes are increasingly recognized as a contributor to disease development especially in the field of dementias. Therefore, the rationale for using metformin is its potential to slow aging processes by acting on mitochondrial metabolism and insulin signaling. Slowing the aging process will be beneficial because quality of life could be improved in old age by delaying disease.

7A link between diabetes and neurodegenerative diseases is for the most part accepted, although data is not unequivocal, and the exact mechanisms are unclear. A large body of data on metformin use in humans and animals with neurodegenerative diseases exists but metformin's therapeutic use is not yet accepted since the results are often conflicting. These different outcomes are dependent on disease, model system, species and the underlying biological pathways involved, which are now briefly reviewed.

Dementia

8Dementia is a common neurological disease of heterogeneous origin and the most important risk factor is aging. Dementia affects memory and other cognitive functions, interfering with a person's ability to carry out routine daily activities. According to the UN world population prospects, the number of persons aged 60 or over on the globe is estimated to grow approximately four times over the next 30 years bringing the prediction that diagnoses of dementia will also rise. The most common form of dementia is AD but there are other types of dementia including vascular dementia, mixed dementia, frontotemporal dementia, dementia with Lewy bodies, and Parkinson's disease dementia.

Alzheimer's disease

9Alzheimer's disease (AD) is the most common neurodegenerative disease, with 45 million people worldwide affected. AD is characterized by progressive memory loss and decline of cognitive function.

10Neurofibrillary tangles (NFTs, composed of abnormal tau protein) and amyloid plaques [composed of extracellular aggregates of amyloid-β (Aβ)] are pathological hallmarks of the AD brain. The NFT protein tau is associated with microtubules and is responsible for their stabilization. Tau pathology and synaptic loss correlates with cognitive impairments in AD patients. The amyloid plaque component Aβ derives from the sequential cleavage of the membrane protein APP (Amyloid precursor protein) by β-secretase BACE1 (β-site amyloid precursor protein cleaving enzyme 1) and the γ-secretase complex. Dysregulation, abnormal modification, and build-up of these protein structures in the brain are thought to be the major pathologies underlying AD.

11From a genetic standpoint, most forms of AD are sporadic and of late onset but familial forms of early onset AD exist and are commonly caused by mutations in APP or presenilin. The underlying biological mechanisms leading to sporadic forms of AD have still not been defined. Inflammatory response, hormone regulation, mitochondrial dysfunction, and lysosomal dysfunction have been implicated, to name only a few processes. There is also growing genetic evidence for microglial involvement. Still, the main risk factors for developing AD are aging, genetic risk factors including being an APOE-ε4 allele carrier, variants in TREM2, and several GWAS loci, traumatic brain injury, cardiovascular risk factors, and several environmental risk factors.

Diabetes and dementia: animal models

12Most of the rodent models used to investigate the role of insulin and glucose metabolism in dementia have focused on AD. Insulin signaling and glucose tolerances are altered in APP/PS1 mice fed a high fat diet, in partially leptin deficient (db/+)-APP/PS1 mice and APP23-(ob/ob) mice. APP load may therefore boost susceptibility to disturbances of energy metabolism.

13A high fat diet induces insulin resistance and promotes amyloidosis and memory impairment in both the Tg2576 mouse model of AD as well as in APP transgenic mice. High fat diets or obesity could contribute to memory deficits even in wild type animals. However, some studies reviewed by Agusti and colleagues had no effect on cognition at all leaving the topic still debated because of conflicting data. Diabetic rats show increased levels of APP, Aβ, and phosphorylated tau. These data suggest that alteration of energy metabolism via insulin signaling may contribute to Aβ generation and altered tau phosphorylation, two well know biochemical events associated with dementias. The modulation of insulin has been proven to be an effective strategy to protect neurons and synapses against toxic Aβ oligomers and to improve cognition in other AD animal models. For example, glucagon-like peptide-1 (GLP-1), insulin-like growth factor 1 (IGF-1) as well as caloric restriction have all been shown to exert neuroprotective effects.

Metformin and dementia: animal models

14Until now only few animal studies have assessed the effect of metformin on cognitive decline and the results are not in line (Table 1). There are many different ways in which researchers can modulate energy metabolism in rodents to try to induce cognitive impairments and perhaps this has contributed to the variable data on metformin in this context. Some animals are fed high fat diets, others such as the (db/db) mice have a spontaneous mutation that cause them to be insulin resistant and obese. In three such high fat diet studies, metformin treatment reduces cognitive deficits, but one study found no improvement. In (db/db) mice, one study found metformin improved memory whereas another study found no effect. It should be noted that in one study looking at normal aging in wild type mice, metformin had a detrimental effect on memory impairment. In this study activation of AMPK by phosphorylation was not measured and therefore it is not clear whether the metformin diet in these animals was optimal. More studies with proper controls are clearly needed to understand the effect of metformin in normal aging.

15It also seems that metformin is capable of simultaneously having both a negative and positive impact on specific biochemical events within the same disease model. For example, in a P301S tauopathy mouse model, metformin treatment reduced tau phosphorylation but promoted tau aggregation. The authors suggest that metformin could be beneficial as a dephosphorylating agent but could promote protein aggregation, the latter being unquestionably the more widely accepted neurodegenerative disease pathology. Similarly, short term metformin treatment again reduced tau phosphorylation but had negative effects since it activates APP and BACE-1. Metformin again seems to have positive effects on reducing total tau and tau phosphorylation at serine 236, whereas the sulfonylurea type diabetes drug glibenclamide performed much better in similar tests.

16Sex may also influence metformin action, which could complicate the interpretation of animal data. Male rodents are often favored and sometimes the sex of the animals used is either overlooked or omitted entirely. In one metformin study already mentioned, male mice showed impaired cognitive function while female mice were improved after treatment.

Diabetes and dementia: human studies

17Changes in cognition have been reported in type 2 diabetes mellitus (T2DM) patients who have not received a diagnosis of dementia and meta-analyses have found moderate but significant deficits across cognitive domains. T2DM also seems to increase the risk of conversion from mild cognitive impairment to dementia and the conversion from amnestic mild cognitive impairment to AD.

18Brain imaging studies in T2DM patients have shown a reduction of whole and regional gray matter volume including hippocampal volume when compared to non-diabetics. Taken together, the clinical data mostly shows that T2DM patients have an increased likelihood of developing dementia. The relationship between diabetes and dementia is further strengthened by reports that reversely, AD patients have an increased risk of developing T2DM or impaired glucose tolerance. Furthermore, post mortem brain pathology in AD shows decreased insulin receptors and IGF protein levels, and insulin levels and markers of insulin signaling are altered in the brain. Hyperglycemia and hyperinsulinemia have also been positively correlated with AD pathology. However, it must be stated that the vast majority of neuropathological studies did not find any association between T2DM or indeed glucose levels and extent of AD pathology and two studies even suggest a negative association.

19One explanation for the discrepancy between clinical and neuropathological studies in AD is the influence of vascular pathology. It is now established that concomitant pathologies in the aging brain are rather the rule than the exception. The fact that most studies show no association between T2DM and Aβ deposition therefore seems to hint that there is no major effect of T2DM on Alzheimer's pathology. An additional effect of small vessel disease on cognition in patients with T2DM and Alzheimer's pathology could explain the higher likelihood to develop dementia in this group. This implies that even if T2DM does not have a large impact on Alzheimer's pathology the proper management of diabetes in AD is relevant. An interplay between T2DM and Alzheimer's beyond vascular pathology should not be disregarded though especially considering evidence on shared pathophysiological features.

Metformin and dementia: human studies

20Results from clinical studies assessing the effect of metformin use on cognitive decline and AD mostly show a positive influence (Table 2). Metformin use is associated with significantly lower risk of cognitive impairment in T2DM. The incidence of dementia in general is lower in T2DM patients receiving metformin, sulfonylurea or a combination of both drugs compared to those not receiving oral anti-hyperglycemic agents. The risk of developing AD was lower in diabetics receiving metformin than in patients receiving sulfonylurea or thiazolidinediones in two studies. However, in a single study, long-term use of metformin for T2DM (though not sulfonylureas or thiazolidinediones) was associated with higher risk of developing AD. One informative study used latent class analysis to identify groups of men with T2DM receiving metformin who develop different profiles of comorbidities including dementia. They concluded that the effect of metformin may in fact differ depending on the risk-profile of patient receiving the drug.

21In an interventional study, Luchsinger and colleagues investigated the effect of metformin given daily for 12 months compared to placebo in overweight patients with amnestic mild cognitive impairment. There was improvement in the selective reminding test in the group receiving metformin but not in other cognitive or biomarker outcomes. The results were only marginally significant and there was no correction for multiple measurements which at least suggests that the observed improvement must be confirmed in an independent trial. In another interventional, short-term metformin study, nondiabetic patients with mild cognitive impairment or mild dementia due to AD took metformin or a placebo for 8 weeks. Those taking metformin significantly improved in a measure of executive function but not in other cognitive tests or biomarkers. Again, a multitude of test was performed without correction for multiple testing.

22Although the majority of data on metformin use in dementia with or without T2DM is generally positive, it should be considered that the effect of metformin likely depends on complex underlying pathological processes and may to some extent be related to an effect on vascular rather than neurodegenerative processes. In some instances, metformin could even exert detrimental effects. Prospective interventional studies have not been able to show convincing evidence of a positive effect of metformin in mild cognitive impairment or mild Alzheimer's dementia but were likely underpowered or of too short duration. More, long-term, controlled metformin studies in large, well-defined dementia cohorts are needed.

Background

23Parkinson's disease (PD) is a common neurodegenerative disease, affecting over 1% of the population above the age of 60 and around 4% older than 85. PD is characterized by bradykinesia and a combination of rigidity, resting tremor, postural instability, and a large range of non-motor symptoms. Like other neurodegenerative diseases, PD is clinically and pathologically heterogeneous, with a large variation in disease onset and progression. Progressive loss of dopamine-containing neurons in the substantia nigra pars compacta, located in the mid brain, results in a deficit of dopamine in the striatum. Insoluble protein inclusions in neurons, termed Lewy bodies, mainly consisting of aggregated α-synuclein (aSyn) are the main neuropathological hallmark of PD. Lewy bodies and protein aggregates are found in multiple brain regions and spread with disease progression. The exact biological mechanism leading to aSyn aggregation and neuronal loss remains unknown and currently only the symptoms of PD are treated with dopamine-replacement therapy and in some cases deep brain stimulation.

24Approximately 5–15% of PD cases can be attributed to disease-causing genetic variants and around 15% of patients have a first degree relative who is also affected. The genetic architecture of PD has been well studied but it is complex. 23 loci and 19 genes have so far been associated with familial forms of PD. Like in most neurodegenerative diseases, the majority of cases probably result from a complex interplay of risk modifying genetic variation, environmental factors and chance. Knowledge about the genes involved in PD have allowed insight into the underlying biological pathways. Together with multiple environmental factors and epidemiological data, the genetic data has highlighted several cellular functions and pathways including mitochondrial dysfunction, lysosomal function, inflammation, build-up of aggregation-prone proteins and oxidative stress.

25Despite large investments in research for neuroprotective compounds for PD, none have so far shown any convincing effects in clinical trials.

Diabetes and PD: animal studies

26Rodent studies have shown that there is a link between insulin resistance and development of PD. A high fat diet enhanced vulnerability to the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) as measured by increased nigrostriatal neurodegeneration and motor deficits. Likewise, in an aSyn mouse model of PD a high fat diet led to an accelerated development of locomotor phenotype and earlier onset of neurodegeneration.

27Insulin resistance can directly interfere with dopamine signaling. Rats fed a high fat diet exhibit impaired nigrostriatal dopamine function and overweight and diabetic mice show degeneration of dopaminergic neurons.

Metformin and PD: animal studies

28Only a handful of rodent studies have so far assessed the effects of metformin as a neuroprotective agent in PD. These studies have focused mainly on metformin treatment in combination with acute MPTP induced parkinsonism. Although experimental designs in these studies are quite similar, the results are variable, arguing against differences in modeling as the major cause of metformin's variable effects. However, differences in the dose and duration of MPTP and metformin treatments may be important (Table 1).

29Most studies in rodents find that metformin reduces the damaging effect of MPTP on dopaminergic neurons, shown by tyrosine hydroxylase staining (a marker for dopaminergic neurons) in the substantia nigra pars compacta, striatum, or both. Two studies suggest that metformin's protective effect may not be specific. A study by Ismaiel and colleagues however, reported that metformin had no protective effect against MPTP-induced neuronal loss in the SN and Bayliss reported no protective effect on dopaminergic neurons in the SN, only in striatum.

30Metformin's supposed ability to protect against dopaminergic neuronal death induced by the neurotoxin MPTP correlates in three studies to improvements in the motor function of rodents. Given that both, MPTP and metformin act on complex 1 of the respiratory chain, a mutual influence of the drugs on mitochondrial survival cannot be excluded. It is possible that in these studies metformin primarily reduced the damaging effects of MPTP itself rather than restoring damaged neurons. Therefore, examination of metformin's action in transgenic mouse models rather than acute toxin models of PD might give better insight about its potential. An interesting first hint comes from a study using healthy non-transgenic mice that showed that metformin could reduce aSyn phosphorylation in the brain.

Diabetes and PD: human studies

31Studies assessing the risk of developing PD in patients with diabetes have very mixed outcomes. In one meta-analysis comprising 14 case-control studies, PD risk was decreased in T2DM patients. Conversely, Cereda and colleagues describe an increased risk for developing PD in diabetics in four prospective cohort studies but not a higher prevalence of diabetes in in patients with PD in five case-control trials. It has to be noted that the case-control trials with the largest populations did consistently show a similar of even higher prevalence of diabetes in PD compared to controls. More recently a meta-analysis including seven population-based cohort studies which also found an increased PD risk in patients with diabetes. Taken together the meta-analyses seem to hint toward an increased incidence of PD in T2DM. A potential pitfall is the inclusion of vascular PD in some of the studies. T2DM does contribute to cerebral small vessel disease and therefore non-exclusion of patients with vascular lesions may skew the results toward more patients with T2DM exhibiting signs of parkinsonism. This particular problem was addressed in some studies showing an increased incidence of PD in T2DM and therefore cannot sufficiently explain the discrepancies. From a neuropathological view one study describes an association between increased blood glucose levels with increased risk of Lewy body formation in the substantia nigra pars compacta and locus coeruleus further supporting a role of T2DM in the pathogenesis of PD.

32Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common causes of dementia in the elderly. PD patients with T2DM are reported to have a greater rate of cognitive decline and lower gray matter and white matter volume, although the group was small. PDD patients are more likely to show insulin resistance in an oral glucose-tolerance-test than PD patients without dementia. DLB and PDD were less common in patients with diabetes in one study using data from the Swedish Dementia Registry, yet T2DM was not significantly associated with PDD in many others.

Metformin in PD: human studies

33Clinical studies have not looked solely at metformin, but rather metformin compared to, or in combination with other oral anti-hyperglycemic agents (see Table 2). Taken together all the studies look at different medications and are hardly comparable. There is lack of clinical data that suggests a positive effect of metformin on PD risk. Wahlqvist and colleagues tried to determine the effect of sulfonylurea, metformin or a combination of both drugs on the incidence of PD in patients with T2DM. Patients with T2DM receiving sulfonylurea had an increased PD risk compared to those not receiving oral anti-hyperglycemic agents. Metformin alone or in combination with sulfonylurea had no impact, suggesting that metformin might rescue the harmful effect of sulfonylurea.

34Brakedal and colleagues compared the incidence of PD in patients with T2DM from the Norwegian Prescription Database (NorPD) receiving glitazones with or without metformin or metformin alone. Patients taking glitazones had a significantly lower incidence of PD compared to patients on metformin alone. There was no risk reduction in past users of glitazones, indicating the necessity of long-term or even permanent exposure to glitazones for risk reduction. Looking at patients from the NorPD receiving statins, metformin or both showed a lower hazard ratio to develop PD for patients using statins in combination with metformin when compared to metformin alone and the risk was lowest in patients only taking statins. The positive effect of statins may come through their anti-inflammatory effect and a reduction of microglial inflammatory response, which has been shown to have a positive effect on striatal dopamine activity. The question why metformin seems to have a positive effect when added to sulfonylurea while it has a negative effect when taken together with statins must be addressed. The combination of T2DM and hypercholesterolemia might increase the risk of developing PD more than hypercholesterinemia alone and this risk may not be lowered sufficiently by a combination of statins and metformin. The addition of metformin to sulfonylurea may result in a better control of T2DM than the therapy with sulfonylurea alone thereby reducing effects that promote PD risk. Also, the complex interplay between the different drugs has to be taken into account.

35To our knowledge there is no data available on metformin use and disease progression. It is also unclear whether metformin use in individuals without insulin resistance may have a beneficial effect on PD development.

Other neurodegenerative diseases

36There are to our knowledge very few or no reports of metformin studies in other, rarer neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Huntington disease (HD), motor neuron disease, or atypical parkinsonian disorders. Here we briefly note relevant studies concerning association with diabetes or use of drugs targeting energy metabolism.

Amyotrophic lateral sclerosis

37ALS is a progressive neurodegenerative disease that is characterized by degeneration of the first and second motor neuron resulting in spasticity and muscle atrophy. Eventually this results in difficulty speaking, swallowing, and breathing and often leads to death within a few years after diagnosis. Neurochemical imbalance and genetic mutations are known to cause ALS, but most cases are sporadic and old-age is an important risk factor. Most drugs available for ALS relieve symptoms only, although the drug riluzole and more recently edaravone have been shown to slow progression of the disease.

38A protective effect of diabetes in older patients and an increased risk of developing ALS in younger patients with diabetes has been described which is thought to reflect differences in association of ALS with T1DM and T2DM. Most studies have shown a decreased risk for developing ALS in patients with T2DM. However, other studies reported no significant effect on ALS risk or progression and even a higher risk of developing ALS in T2DM in patients below 65 years of age. Nutritional status is negatively associated with ALS severity and hypercaloric nutrition has even been suggested as a potential treatment option for ALS. Two trials with the PPAR-γ agonist Pioglitazone (which reduces insulin resistance) have not shown any benefit in disease progression.

Huntington disease

39HD is a progressive neurodegenerative disease that causes choreatic movements, psychiatric symptoms, and cognitive decline. The most common form of the disease is of early onset, usually diagnosed around 30–40 years of age. HD is caused by defects in the gene HTT, which encodes the protein huntingtin and the mode of inheritance is autosomal dominant. Expansion of CAG repeats in the HTT gene leads to the production of an abnormally long version of the huntingtin protein. This results in the protein being broken down by the cell into small, toxic fragments and these protein fragments aggregate and accumulate in neurons causing the disease.

40Altered glucose metabolism and increased rates of T2DM have been reported in patients with HD and a high prevalence of T2DM has been reported in a Chinese family with HD. However, other studies were not able to identify differences in oral glucose tolerance test or pancreatic tissue between HD patients and controls. HD patients with T2DM receiving metformin had better cognitive test results than HD patients without diabetes not taking metformin. This was in stark contrast to the non-HD control group where people with T2DM taking metformin fared worse in the cognitive test compared to non-diabetic controls.

Metformin: mechanism of action in neurodegenerative diseases

41The in vivo studies conducted so far, regarding the effect of metformin have generated conflicting results. Besides the large differences in study design, these outcomes are probably also due to the many biological pathways influenced by metformin. Here we will discuss some of the biological signaling pathways and biological mechanisms that are the most relevant for metformin's potential as a therapy in neurodegenerative disease (Figure 2).

Central metabolism and signaling

42Central metabolism is tied to the overarching cell signaling pathways involved in proliferation, stress and survival, which are heavily implicated in human diseases including cancer and neurodegeneration. Metformin acts on central metabolism and several major signaling pathways including energy sensing (glucose metabolism and AMPK signaling), mTOR signaling, and inflammatory signaling. Mitochondrial signaling will be addressed separately.

Energy sensing and metabolism

43The brain constitutes only 2% of the total body mass, but it is one of the main energy-demanding organs in the human body utilizing around 20% of total energy expenditure. Brain cells incorporate (i) the neurons (70–80% of brain energy expenditure) and (ii) glial cells, comprising oligodendrocytes, astrocytes and microglia (accounting for the remaining 20–30% of energy expenditure). The high energy demand of neurons is one of several factors partially explaining the selective vulnerability of certain neuronal subtypes in neurodegenerative diseases. Energy metabolism has long since been thought to play a role in the etiology of neurodegenerative diseases and here we will briefly mention some of the related signaling pathways and biological mechanisms that are relevant for metformin's therapeutic potential in neurodegeneration.

AMPK signaling

44AMPK is an evolutionarily conserved sensor of cellular energy status. AMPK is activated by increasing AMP levels in conditions of energy deprivation and the enzyme consequently inhibits energy consumption and stimulates catabolic pathways. Activation of AMPK has a wide range of effects, including inhibition of mTor and PI3K-Akt signaling (two important pathways discussed later).

45Dysregulation of AMPK is associated with insulin resistance and T2DM and neuroinflammation. AMPK signaling plays a major role in AD disease progression since AMPK has been shown to regulate both Aβ generation and tau phosphorylation. Inhibition of Aβ production and tau phosphorylation in neuronal cultures is dependent on AMPK activation and activation of AMPK lowers extracellular Aβ accumulation. Conversely, in neurons, AMPK activation has been linked to tau phosphorylation as a response to Aβ toxicity.

46Metformin inhibits complex I of the electron transport chain needed for mitochondrial respiration, thereby leading to an energy deficit and indirectly activating the AMPK pathway. Thus, stimulation of AMPK can be seen as a key consequence of metformin administration, explaining many of the known effects of the drug (Figure 3).

47However, in the context of AD especially, more studies are needed to understand the complex role of AMPK signaling and the action of metformin. A study conducted in human neuronal stem cells proposed that activation of AMPK via metformin is neuroprotective against Aβ and other in vitro studies showed that metformin is able to reduce tau phosphorylation via mTOR/PP2A (Protein phosphates 2A) signaling and that it can reduce molecular pathologies associated with AD. An additional level of modulation via AMPK by metformin could come from metformin's ability to reduce BACE1 protein levels in neurons. Conversely, metformin was also reported to upregulate BACE1 in neurons and increase the generation of Aβ, suggesting detrimental effects of activating AMPK in diseased neurons.

48In PD mouse models the AMPK involvement is similarly multifarious. Administration of the neurotoxin MPTP activates AMPK signaling. Interestingly, both AMPK overexpression and AMPK inhibition have promoted survival in neurotoxin treated PD models but another study provided evidence for a protective function of AMPK activation in in vivo PD models.

49Overexpression of aSyn in cell culture reduced AMPK activity, while inhibition of AMPK lowered resistance to aSyn toxicity. AMPK's subunits α1 and α2 have neuroprotective effects against aSyn toxicity with low but continuous AMPK activity almost completely preventing loss of dopaminergic neurons. Accordingly, in rodent PD models dietary metformin influenced neuronal function via AMPK modulated aSyn phosphorylation status. However, several other studies point in a different direction. Over-active AMPK promotes aSyn accumulation and hyperactivation of AMPK leads to aSyn binding to the GTPase PIKE-L and dopaminergic cell death. These studies show that lower AMPK activity may in fact be beneficial at least in aSyn models of PD.

50As is the case in many neurodegenerative diseases, the underlying genetic and biological causes are heterogeneous, often causing multiple pathologies that can overlap across the disease spectrum. The action of metformin primarily via the mitochondria could have numerous and potentially opposite effects on AMPK depending on the amount of involvement and type of mitochondrial signaling in each patient or disease model at any given moment. One important aspect to consider here is that biological pathways are not necessarily fixed in a single state throughout the disease course. Neurons especially have evolved to carefully adapt to energetic needs in order to survive since they are seldom replaced. Sophisticated compensatory mechanisms are initiated for the purpose of mitochondrial rejuvenation and adaption. Such complexity has made modeling neurodegenerative diseases in human neurons challenging and has contributed to the current situation where no causative or “cure all” therapies are available.

Glucose metabolism

51Glucose is an essential energy substrate needed to sustain neuronal activity and is taken up via glucose transporters expressed in the brain endothelium, astrocytes, and neurons. Neurons mostly rely on glucose for energy but utilize ketone bodies during fasting. In contrast to other cell types, in neurons the rate limiting glycolytic enzyme Phosphofructokinase B3 is highly turned over by the proteasome, resulting in the preferential metabolism of glucose via the pentose phosphate pathway (PPP) as opposed to glycolysis.

52A product of the PPP is the electron donor NADPH, which provides reducing power for anabolic reactions and is crucial for maintaining antioxidant potential. The PPP helps neurons to meet high energy demands, but since neurons are predominantly oxidative, maintaining a fine balance between glycolysis and PPP is essential for counteracting oxidative damage and conserving energy.

53Glial cells on the other hand, predominantly metabolize glucose via glycolysis producing lactate and have only very low rates of mitochondrial oxidation. Glia metabolically support axons and lactate can be shuttled across a gradient from glia to neurons (Figure 2). Interestingly, in cell culture, neurons favor lactate over glucose preferring a fast supply of energy over metabolic efficiency. In the human brain, energy demand must be tightly regulated to offset oxidative damage and therefore cell culture and cell culture media effects should be taken into consideration when considering the conflicting data on metformin performed in situ.

54Inhibiting the PPP and glutathione pathways causes increased levels of oxidative stress and cell death similar to that seen during neurodegeneration. Glucose hypometabolism has been shown in PD brains and deregulation of glucose metabolism has been proposed as an early event in the pathogenesis of PD. Dunn et al. proposed that dysregulation of glucose metabolism occurs via dysregulation of the PPP, which causes oxidative stress because of less efficient glutathione recycling, and it is this event that underlies the increased levels of oxidative stress observed in PD.

55Metformin can act in these pathways by slowing oxidative phosphorylation via inhibition of complex I in mitochondria and by inhibiting gluconeogenesis, having the effect of further aiding neurons to reduce their oxidative burden by minimalizing NADH utilization.

Insulin signaling

56Insulin plays an important role in the brain. It is used as a hormonal signal to control body weight, food uptake, and metabolic homeostasis. Insulin has also been shown to influence expression of dopamine receptors and concentration of dopamine. Disturbances in insulin signaling have been implicated in several neurodegenerative diseases including AD, PD, and HD. Insulin is secreted in response to high blood sugar and acts in different organs including the brain. Activation of the Phosphoinositide-3-kinase (PI3K)—Akt pathway via insulin receptor activation and insulin receptor substrates plays a central role in the metabolic actions of insulin. Akt activation regulates proteins such as mTOR, FOXO, and BAD. Overall, Akt has over 100 known substrates and has diverse effects on cellular growth, cell proliferation, glucose uptake, protein synthesis, glycogen synthesis, and apoptosis. Akt is inhibited by PP2A, PHLPP1/2, and indirectly by PTEN. Insulin resistance has been associated with disturbances in signaling up and downstream of Akt.

57Insulin has been administered to patients to try to improve symptoms of neurodegeneration and has been shown to protect cells from Aβ induced death. The Insulin Degrading Enzyme (IDE), originally found to play an important role in insulin turnover is involved in Aβ degradation. IDE can degrade secreted Aβ from neurons and microglia and mediate its clearance. Furthermore, IDE hypofunction can contribute to in vivo Aβ accumulation. In hippocampi of ApoE4 carriers reduced expression levels of IDE have been measured and genetic differences in IDE expression and activity have been suggested to be involved in AD development. Reduced levels of IDE in liver and brain have been correlated with aging and IDE can counteract damage from oxidative stress, suggesting a neuroprotective role.

58Metformin lowers blood glucose levels through inhibition gluconeogenesis in the liver via AMPK. AMPK inhibits PI3K/Akt signaling, the crucial pathway downstream of the insulin and IGF1 receptors. Metformin has also been shown to act on insulin signaling independently of AMPK. Metformin is reported to downregulate expression of insulin and IGF-1 receptors and reduces phosphorylation of insulin receptors including IRS-1.

59Both acute and chronic metformin administration has been found to increase levels of GLP-1, an incretin known to induce insulin secretion, in humans and mice. Very recently a randomized, double-blind, placebo-controlled trial for PD showed that a GLP-1 agonist had positive effects on motor symptoms in PD, generating a new potential mechanism for metformin action in neurodegeneration.

mTOR Signaling

60mTOR signaling is a highly conserved and central signaling pathway integrating upstream signals such as nutrient and redox status and then controlling downstream processes such as cellular growth, motility, survival, and death. The mTor pathway is crucial for regulating mitochondrial biogenesis and autophagy, two processes that are defective in many neurodegenerative diseases.

61mTOR is a serine/threonine protein kinase, composed of the protein complexes mTORC1 and mTORC2. mTOR signaling is targeted by the PI3K/Akt pathway, the key insulin signaling pathway. Both PTEN and AMPK suppress mTor signaling and rapamycin is a well-studied inhibitor of mTORC1. Although mTor signaling influences many downstream events, the most important mechanism of action is through the phosphorylation and activation of S6K1 and 4E-BP1 and subsequent control of RNA translation (Figure 4). Interestingly, deficiency in mTor signaling has been implicated with insulin resistance and diabetes. Nutrient dependent stimulation of S6K1 can induce insulin resistance and S6K1 deficiency protects against high fat diet-induced insulin resistance.

62The mTOR inhibitor rapamycin suppresses neurodegeneration phenotypes in mice and protects against MPTP-induced loss of dopaminergic neurons. Rapamycin also prevents the development of dyskinesia without affecting the therapeutic efficacy of L-DOPA and thus, the mTORC1 signaling cascade represents a promising target for the design of anti-Parkinsonian therapies.

63Elevated mTOR signaling has been found in AD patients and is linked to diabetes and aging. Rapamycin abolishes cognitive deficits and reduces Aβ levels in a mouse model of AD. It also ameliorates AD-related phenotypes by restoring hippocampal gene expression signatures. Importantly, mTor regulates tau phosphorylation and degradation, making this pathway an interesting target for the treatment of tauopathies.

64If we compare the therapeutic potential of metformin, a well-known inhibitor of mTOR signaling through activation of AMPK to that of rapamycin, which is more widely accepted in the field, the obvious difference is that metformin action on mTOR is relatively indirect. Rapamycin forms a complex with the FKBP12 binding protein which binds and specifically alters mTORC1. Metformin acts on the mTOR pathway indirectly via multiple routes. The AMPK independent routes include inhibition of transcription factors, the PI3K/AKT pathway, and induction of REDD. In direct contrast to this, one study has shown that metformin can directly inhibit mTORC1 and is dependent on Rag GTPases not AMPK. These data support the view that metformin has more than one direct target and is likely to have many more indirect targets, thus explaining why the use of metformin and a research tool or treatment is less accepted than rapamycin.

65Nevertheless, the mTOR pathway links several biological pathways underlying neurodegenerative diseases and therefore the ability of metformin to inhibit this signaling cascade endorses the argument that more mechanistic work using metformin and its inclusion in clinical trials should be positively considered.

Inflammation

66Neuroinflammation is considered a major driving force in the progression of neurodegenerative diseases and the triggering of innate immune mechanisms is emerging as a crucial component in disease pathogenesis. Microglia and other cell types in the brain can be activated in response to misfolded proteins or aberrantly localized nucleic acids. This diverts microglia from their physiological and beneficial functions, and leads to their sustained release of pro-inflammatory mediators.

67Intake of non-steroidal anti-inflammatory drugs (NSAIDs) has been reported to decrease incidence of AD later in life and activated microglia are found in brains of AD patients.

68In AD, an integrated network-based approach identified gene perturbations associated with innate immune pathways and microglia cells in late onset forms of the disease. AD patients show increased expression of inducible nitric oxide synthase (iNOS, a product of neuroinflammation) in neurons and glia, leading to augmented nitric oxide production. Activated microglia can further induce tau phosphorylation in primary mouse neurons, activating IL1β receptor and p38 MAPK stress signaling.

69In PD, patients show increased numbers of activated microglia and astrocytes and microglia activation has been associated with disease progression. aSyn has been found to activate microglia, enhancing neurotoxicity. Activation of microglia increases nitration of aSyn, resulting in neuronal cell death.

70Immune signaling triggers transcriptional events, but also changes in metabolic flux, redox balance, and metabolite balance via mitochondria. Mitochondrial dysfunction is associated with neuroinflammation and even moderate mitochondrial DNA stress can trigger antiviral signaling.

71Metformin reduces general inflammation parameters and inhibits NF-κB signaling as well as proinflammatory cytokines in different cell types, suggesting that metformin could protect against neuroinflammation. Interestingly, in two MPTP-induced PD mouse models, metformin reduced levels of the microglia marker Iba1 as well as the pro-inflammatory cytokines TNFα, Il-1β, IL-6, and iNOS in the substantia nigra pars compacta. Here, more studies are needed but metformin seems to have a wholly positive effect against general inflammation. Neuroinflammation is a recognized event associated with neurodegenerative diseases and therefore metformin could be both a useful tool and therapy.

Mitochondria

72Mitochondria are crucial organelles that produce energy and perform a plethora of other functions needed for central metabolism and cell signaling. Mitochondrial dysfunction is a phenomenon that traverses all neurodegenerative diseases and forms the basis of β-cell dysfunction in T2DM. One important aspect of mitochondrial dysfunction in neurological disease is that the need for tightly controlled energy metabolism in neurons can partially explain some of the vulnerabilities involved in their demise.

Parkinson's disease

73In PD, the link between mitochondrial dysfunction and disease has been proven by the identification of environmental factors and disease genes which critically affect mitochondria. The outcome has been a large body of work depicting the role of mitochondrial dysfunction in PD, yet the exact mechanisms underlying sporadic forms of PD are less defined.

74Loss of function mutations in PINK1 or parkin cause PD as a result of mitochondrial dysfunction and this has been elucidated in vitro and in vivo. PINK1 and parkin act in a pathway that is important for mitophagy (removal of damaged mitochondria via the lysosome) induced by mitochondrial depolarization. Here, PINK1 functions upstream of parkin. Upon mitochondrial damage, PINK1 accumulates on the mitochondrial surface and selectively recruits parkin to mitochondria. Mitochondrial substrates are ubiquitinylated, leading to the removal of damaged mitochondria. PINK1 is now known to be a ubiquitin kinase but may have other functions yet unknown. For example, PINK1 is not required for basal mitophagy in vivo and has been proposed to regulate complex I, mitochondrial dynamics, mitochondrial proteostasis, and mitochondrial metabolism via TRAP1.

75PINK1 and parkin are upregulated under metabolic stress in the vessel walls of obese and diabetic mice and have a protective action by limiting reactive oxygen species (ROS) production and mitochondrial dysfunction. In a diabetic mouse model, PINK1 expression in the hippocampus was in this case reduced following hydrogen peroxide treatment, further suggesting that PINK1 plays a role as a stress sensor and functions accordingly in diverse ways. PINK1 is generally associated with neuroprotection since loss of function causes PD, but because PINK1 is normally highly turned over at the mitochondrial outer membrane and therefore overexpression and/or altered expression might also induce unwanted downstream events. In one study, PINK1 overexpression restrained MAPK and ROS signaling and mitigated insulin resistance in cell models. Conversely, PINK1 loss corrupts function of islet and β-cells causing impaired glucose uptake and increased levels of plasma insulin. Further evidence that PD proteins play important roles in energy metabolism is a study showing that TP53INP1 deficient cells (TP53INP1 is a susceptibility locus in T2DM) causes an increase in ROS that impairs mitophagy via the PINK1-parkin pathway.

76Parkinson's disease mutations in aSyn are associated with several cellular defects, including reduced mitochondrial integrity and function. Recent work has identified a highly neurotoxic aSyn species which induces mitochondrial damage and mitophagy in the human and animal brain. However, the consequences of these mitochondrial changes for bioenergetic functions remains somewhat undefined. Interestingly, aSyn toxicity is mitigated by TRAP1, a mitochondrial ATPase that has been linked to metformin.

77In this pathway, TRAP1 and the mitochondrial serine protease HtrA2 are both targets of the PD protein PINK1. HtrA2 and TRAP1 genetic variants have been found in PD patients but the mutations are rare and a controversial topic. Regardless of the genetic contribution to disease, TRAP1 at least appears to play an important regulatory role in mitochondria that is relevant for the fine tuning of energy metabolism. TRAP1 is well studied in cancer since TRAP1 expression is tightly regulated in tumor cells, TRAP1 acts as a metabolic switch by targeting and inhibiting succinate dehydrogenase, which is important for metabolic re-purposing and inflammatory responses.

78In ovarian cancer where TRAP1 expression was altered, metformin was effective in rendering the tumor sensitive to chemotherapy, suggesting that metformin might be relevant to TRAP1 mediated signaling. On this basis, metformin was then used to successfully rescue mitochondrial dysfunction in a TRAP1 cell model of PD. In a healthy person, fine tuning of mitochondrial energy usage via the PINK1-HtrA2-TRAP1 pathway and other regulatory mechanisms may allow cells to conserve energy and reduce oxidative burden. Metformin's ability to mimic this fine tuning role in vitro was beneficial in one model of sporadic PD. However, there are still a lot of questions that remain unanswered such as whether metformin is beneficial in non-diseased neurons, aging neurons and other forms of familial and sporadic PD. One question is whether metformin could specifically target energetic deficits in the dopaminergic neurons of the substantia nigra pars compacta. The question is not yet answered because selective vulnerability is still not yet fully understood. We can speculate that oxidative or metabolic burden over time could contribute to making these cells especially vulnerable. Many redox reactions happen in mitochondria as a result of mitochondrial activity. Neurons in comparison to many other cell types have a high energy demand and because of the autonomous pacemaking in dopaminergic neurons of the substantia nigra, these cells are thought to have a higher oxidative burden. The metabolism of dopamine itself is highly oxidative and can form several toxic species. Therefore, if metformin can mildly reduce the oxidative burden at the mitochondria without interfering with normal redox signaling and stimulate autophagy and other processes which can become less effective over time, it could be seen as a very useful drug to counteract neurodegenerative diseases. Neurons have a sophisticated and unique line of quality control defenses which allow them to compensate for stress and survive against all odds because once they die, inflammation often ensues and they are seldom replaced. It just depends whether metformin treatment could be used to intervene at the right time to not interfere with necessary compensatory responses, rather enhance them.

Alzheimer's disease

79The exact mitochondrial events leading to AD are less defined than in PD, yet aging is still the greatest known risk factor. Energy metabolism and mitochondrial dysfunction have been proposed as a primary event in mechanisms underlying AD such as synaptic degeneration, Aβ deposition and formation of neurofibrillary tangles. There is a vast amount of evidence that mitochondrial dysfunction occurs after the early cellular events in AD and can contribute to the advancement of further degeneration, but it is often unclear whether mitochondrial dysfunction is indeed just a secondary event or whether it might be involved in primary pathogenesis. For example, in the case of tau, abnormal tau triggers oxidative stress and mitochondrial defects such as mitochondrial depolarization, impaired mitochondrial complex activities and reduced energy output. Tau also localizes to the microtubules, the tracks on which mitochondria move along with the help of adapter proteins and defective mitochondrial movement has been shown in several models of AD.

80There is also evidence that mitochondrial metabolism is altered in AD brains (reviewed in). The tricarboxylic acid (TCA) cycle enzymes pyruvate dehydrogenase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase are affected in AD brain tissue and in patient-derived fibroblasts. Changes in these checkpoint TCA cycle enzymes are associated with metabolic re-wiring often in response to stress and redox changes. In addition to matrix enzymes, deficiencies in oxidative phosphorylation (OXPHOS) have been reported [reviewed in].

81In AD research, there are few mechanistic models for mitochondrial dysfunction, mainly due to the fact that there are no mitochondrial causative genes for AD. The mitochondrial mechanism of metformin action in dementia and AD is likely similar in PD, in that metformin can act on mitochondrial quality control via mitochondrial biogenesis and energy conservation.

The complex I paradox

82Many of metformin's actions are thought to be an indirect result of complex I inhibition. The exact inhibitory mechanism of metformin on complex I is not fully understood. The inhibitory mechanisms of other complex I inhibitors such as MPTP and rotenone are better known in terms of binding site and mechanism of toxicity, especially in disease.

83Complex I deficiency has long since been associated with mitochondrial dysfunction and Parkinson's disease risk [for a review see]. Complex I deficiencies have also been reported in AD, HD and ALS. The neurotoxins MPTP and rotenone inhibit complex I and generate toxic levels of ROS, which leads to neuronal cell death. It is possible that sub-lethal concentrations of mitochondrial inhibitors that do not generate ROS (or generate less ROS) could be beneficial but little is known.

84It is generally accepted that metformin does not generate dangerous levels of ROS. Pharmacologically reducing oxidative phosphorylation and thus the oxidative burden (at the right moment) without generating too much ROS is certainly a challenge. We found that sub lethal concentrations of the specific mitochondrial complex V inhibitor oligomycin, could rescue mitochondrial dysfunction in a TRAP1 deficient PD model to a similar extent as metformin but since metformin is an approved compound for human consumption, we followed up the protective effects of metformin only. It might be interesting to assess the potential neuroprotective action and toxicity with a titration of several respiratory chain inhibitors that act at different sites. For example, the mitochondrial complex III inhibitor, antimycin A is known to generate large amounts of ROS, but oligomycin and other disrupters of the respiratory chain have been shown to generate little or no ROS.

Aging

85The main hallmarks of aging set out by Lopez-Otin are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. All of these hallmarks in one way or another are associated with the pathogenesis of neurodegenerative diseases. Here we will focus attention on some specific aspects relating to these hallmarks that could be the most relevant to metformin's mechanism of action at the mitochondria.

Mitonuclear protein imbalance

86Human mitochondrial DNA (mtDNA) is bound inside nucleoid bundles, has a high copy number, is inherited maternally and has a high mutation rate. Mitochondrial damage and/or depletion induces stress-signaling and adaptive metabolic responses. MtDNA instability is a physiologically relevant stress observed in many human diseases and aging. Mitonuclear protein imbalance, is a stoichiometric imbalance between nuclear and mitochondrially encoded proteins and is activated as a key longevity response across many species. Alterations to mtDNA are directly linked to respiratory chain dysfunction in sporadic PD patients and it has been shown that complex I is initially affected followed next by complex IV. It is thought that imbalance in the stoichiometry between mitochondrially translated proteins and nuclear encoded ones is both a cellular signal and marker of mitochondrial adaption. The mTOR inhibitor rapamycin is used as a tool to initiate mitonuclear protein imbalance and metformin is capable of modulating mitonuclear protein imbalance in human cells.

Oxidant stress and senescence

87The production of reactive species is usually balanced by the cell's antioxidant defenses. An imbalance in the amount of ROS to antioxidant defense results in oxidative stress and can cause damage to proteins, lipids and nucleotides.

88Mitochondria are a major source of ROS due to oxygen use in energy production through the electron transport chain. Electrons leak while they are being transferred along the complexes of the electron transport chain. Leaked electrons can react with molecular oxygen to form superoxide radicals. Superoxide can react with Mn-SOD to form hydrogen peroxide, a ROS and a signaling molecule. Hydrogen peroxide is either broken down to form water or it can react with metals to form the highly reactive hydroxyl radical. In mitochondria the main leakage sites are at the transfer of four electrons to oxygen at Complex IV, but also complex I, complex III and via certain dehydrogenases of the TCA cycle in the mitochondrial matrix. Consequences of oxidative stress include proliferation, adaption, damage, senescence, or death depending on the cell type and severity [for review see]. Neurons need to counteract a great deal of ROS because of high energy bursts and catecholamine neurotransmitter metabolism.

89Oxidative damage is a major contributor to neurodegenerative diseases [for a review see]. Both oxidative stress and oxidative damage can lead to stress adaption. One such adaptive mechanism in mitochondria might be finely-tuned inhibition of respiratory complexes or mitochondrial uncoupling via uncoupling proteins. There is mounting evidence that mitochondrial uncoupling proteins are neuroprotective [for a review see]. Cellular senescence can occur when adaptive responses are unable to properly protect key molecules from damage to the extent that a cell can no longer divide.

90The PD protein DJ-1 provides a link between neurodegeneration and energy metabolism. DJ-1 acts as a chaperone and protease to stabilize mitochondria and protect cells from oxidative stress. Several other cellular functions have been attributed to DJ-1, including; binding of Ras as a transcriptional co-activator, negative regulation of the phosphoinositide-3-kinase (PI3K)/AKT signaling cascade through inhibition of PTEN, chaperone function, and RNA binding. Although controversial, DJ-1 has also been claimed to have glyoxalase and deglycase enzyme activities. DJ-1 also influences insulin secretion as well as β cell viability in the pancreas and DJ-1 knockout mice show increased ROS levels in islet cells, impaired glucose tolerance and decreased insulin secretion.

Gaps in the research

91Trials using metformin to treat or protect against neurodegenerative diseases in humans and animals have produced mostly conflicting results. The data shows either positive, no or even detrimental effects of metformin on neurodegenerative processes in cell cultures, animals and humans.

92The outcome may depend on the species, cell type or underlying metabolic state. Two promising research areas however are neuroinflammation and aging, yet more work is needed. Very few studies have looked directly at the role of metformin in neuroinflammation, but since this is a growing research focus in the field, more metformin studies may arise. The exact role of metformin in aging is a question that needs to be at least partly understood before we can progress further in understanding its potential to treat neurodegenerative diseases. A major hurdle to this is the lack of good human aging models mainly in vitro but also in vivo.

93Another gap in the knowledge is whether there are potential adverse effects of metformin use in non-diabetics. For example, it has been well documented that long term metformin use leads to vitamin B12 deficiency. Vitamin B12 and folate are needed for transmethylation and hydroxylation reactions from amino acids that are crucial for neurotransmitter biosynthesis. How much influence could this have in a patient with disturbed neurotransmitter metabolism and/or those receiving other medications.

The therapeutic potential of metformin: feasibility

94There are several reasons why the use of metformin to treat neurodegeneration could bring about doubt from clinicians and scientists when considering its potential as a therapy or as a research tool. The main point being that metformin seems to be acting on a plethora of biological pathways, and therefore it is very difficult to pin down mechanisms. The second point is the controversial subject of “anti-aging” drugs in general. Since we know very little about the biological underpinnings of aging and know even less about how to efficiently model it in the laboratory, the promotion of an “anti-aging” drug often conjures up more questions than it answers. Then there are several other sticking points among researchers, one being the fact that metformin acts by inhibiting mitochondrial respiration, the exact effect that has been shown by years of research in the Parkinson's disease field to in fact contribute development of disease.

95In direct contrast, there are several arguments for metformin being a feasible and useful drug. Firstly, glucose metabolism is of central importance to neuronal redox status, therefore to the long-term survival of neurons. Secondly, as a population we are increasingly insulin resistant and therefore metformin is particularly apt. Metformin is a cheap and safe drug with few side effects and therefore more work in vitro, in vivo and in trials will be welcomed.

96Nir Barzilai, the director of the Institute for Aging Research at the Albert Einstein College of Medicine suggests that metformin and other related drugs can extend our years of healthy, disease-free living by decades. Other scientists have not specifically mentioned metformin but in his 2005 book on mitochondria, Nick Lane suggests that if we live longer to rid ourselves of diseases of old age we need more mitochondria and perhaps a more refined free-radical detection system. Whether metformin is capable of modifying the detection system at the right physiological moment without deleterious effects is at least an exciting possibility.

Future developments in the field

97There is potential that metformin could be beneficial in the task of counteracting aging and clinical studies imply that metformin may have positive effects on cognition in T2DM patients. A better understanding of how metformin works will help researchers in the neurodegeneration field to successfully design future research and trials. Upcoming studies such as TAME will help in this respect.

98The anti-aging effects of metformin could be summarized by its ability to interfere with the multistage process of energy production without producing damaging amounts of ROS. This action alone could be seen as neuroprotective and metformin may further protect by activating other biological pathways. For example, slowing mitochondrial energy production can also trigger a cascade of signaling events in the liver that result in reduced glucose and insulin. The key role of insulin in nutrient sensing which balances growth and proliferation with life-extending conservation, makes metformin an interesting drug. The field of aging research is growing and in vivo and in vitro aging models are advancing.

99Probably due to the complexity of metformin action, this drug will not likely serve as a potential treatment for neurodegenerative diseases on the current stage because much more work is needed to understand the role of aging in different neurodegenerative disease forms. The greatest value of metformin today might lie in its potential to help decipher those mechanisms underlying neurodegeneration.

Author contributions

100CR, GM, and JF contributed equally to the writing and the editing of the manuscript. All authors approved the final version and submission of this article.

Conflict of interest statement

101The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 358

1.
Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015 · 2017
No notice
2.
Goodarzi MO Bryer-Ash M. Metformin revisited: re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab. (2005 ) 7:654–65.
Not in our library10.1111/j.1463-1326.2004.00448.x (opens in a new tab)
3.
Viollet B Guigas B Sanz Garcia N Leclerc J Foretz M Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci. (2012 ) 122:253–70.
Not in our library10.1042/cs20110386 (opens in a new tab)
4.
Lamanna C Monami M Marchionni N Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab (2011 ) 13:221–8.
Not in our library10.1111/j.1463-1326.2010.01349.x (opens in a new tab)
5.
Metformin: an old but still the best treatment for type 2 diabetes · 2013
No notice
6.
Patrone C Eriksson O Lindholm D. Diabetes drugs and neurological disorders: new views and therapeutic possibilities. Lancet Diabetes Endocrinol. (2014 ) 2:256–62.
Not in our library10.1016/s2213-8587(13)70125-6 (opens in a new tab)
7.
Mertens J Paquola ACM Ku M Hatch E Bohnke L Ladjevardi S. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell (2015 ) 17:705–18.
Not in our library10.1016/j.stem.2015.09.001 (opens in a new tab)
8.
Kim Y Zheng X Ansari Z Bunnell MC Herdy JR Traxler L. Mitochondrial aging defects emerge in directly reprogrammed human neurons due to their metabolic profile. Cell Rep. (2018 ) 23:2550–8.
Not in our library10.1016/j.celrep.2018.04.105 (opens in a new tab)
9.
Craft S Stennis Watson G. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. (2004 ) 3:169–78.
Not in our library10.1016/s1474-4422(04)00681-7 (opens in a new tab)
10.
Ninomiya T. Diabetes mellitus and dementia. Curr Diab Rep. (2014 ) 14:487.
Not in our library10.1007/s11892-014-0487-z (opens in a new tab)
11.
Neumann KF Rojo L Navarrete LP Farias G Reyes P Maccioni RB. Insulin resistance and Alzheimer's disease: molecular links & clinical implications. Curr Alzheimer Res. (2008 ) 5:438–47.
Not in our library10.2174/156720508785908919 (opens in a new tab)
12.
Verdile G Fuller SJ Martins RN. The role of type 2 diabetes in neurodegeneration. Neurobiol Dis. (2015 ) 84:22–38.
Not in our library10.1016/j.nbd.2015.04.008 (opens in a new tab)
13.
United Nations DoEaSA Population Division World population prospects: The 2015 revision, key findings and advance tables. In: Working Paper No ESA/P/WP241 (2015 ).
Not in our library
14.
Prince M Comas Herrera A Knapp M Karagiannidou M Guerchet M World Alzheimer Report 2016: Improving Healthcare for People with Dementia. Coverage, Quality and Costs Now and in the Future. London: Alzheimer's Disease International (ADI) (2016 ).
Not in our library
15.
Brion JP Couck AM Passareiro E Flament-Durand J. Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study. J Submicrosc Cytol. (1985 ) 17:89–96.
Not in our library
16.
Grundke-Iqbal I Iqbal K Tung YC Quinlan M Wisniewski HM Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA. (1986 ) 83:4913–7.
Not in our library10.1073/pnas.83.13.4913 (opens in a new tab)
17.
Glenner GG Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. (2012 ) 425:534–9.
Not in our library10.1016/j.bbrc.2012.08.020 (opens in a new tab)
18.
Johnson GV Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci. (2004 ) 117:5721–9.
Not in our library10.1242/jcs.01558 (opens in a new tab)
19.
Arriagada PV Growdon JH Hedley-Whyte ET Hyman BT Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology (1992 ) 42:631–9.
Not in our library10.1212/wnl.42.3.631 (opens in a new tab)
20.
Sun X Bromley-Brits K Song W. Regulation of beta-site APP-cleaving enzyme 1 gene expression and its role in Alzheimer's disease. J Neurochem. (2012 ) 120(Suppl). 1:62–70.
Not in our library10.1111/j.1471-4159.2011.07515.x (opens in a new tab)
21.
Goate A Chartier-Harlin MC Mullan M Brown J Crawford F Fidani L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature (1991 ) 349:704–6.
Not in our library10.1038/349704a0 (opens in a new tab)
22.
Levy-Lahad E Wasco W Poorkaj P Romano DM Oshima J Pettingell WH. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science (1995 ) 269:973–7.
Not in our library10.1126/science.7638622 (opens in a new tab)
23.
Sherrington R Rogaev EI Liang Y Rogaeva EA Levesque G Ikeda M. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature (1995 ) 375:754–60.
Not in our library10.1038/375754a0 (opens in a new tab)
24.
Hardy J Bogdanovic N Winblad B Portelius E Andreasen N Cedazo-Minguez A. Pathways to Alzheimer's disease. J Intern Med. (2014 ) 275:296–303.
Not in our library10.1111/joim.12192 (opens in a new tab)
25.
Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk · 2017
No notice
26.
Huang KL Marcora E Pimenova AA Di Narzo AF Kapoor M Jin SC. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. Nat Neurosci. (2017 ) 20:1052–1061.
Not in our library10.1038/nn.4587 (opens in a new tab)
27.
Kivipelto M Ngandu T Fratiglioni L Viitanen M Kareholt I Winblad B. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. (2005 ) 62:1556–60.
Not in our library10.1001/archneur.62.10.1556 (opens in a new tab)
28.
Coon KD Myers AJ Craig DW Webster JA Pearson JV Lince DH. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J Clin Psychiatry (2007 ) 68:613–8.
Not in our library10.4088/jcp.v68n0419 (opens in a new tab)
29.
Baumgart M Snyder HM Carrillo MC Fazio S Kim H Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimer's Dement. (2015 ) 11:718–26.
Not in our library10.1016/j.jalz.2015.05.016 (opens in a new tab)
30.
Environmental risk factors for dementia: a systematic review · 2016
No notice
31.
Li W Risacher SL McAllister TW Saykin AJ Traumatic brain injury and age at onset of cognitive impairment in older adults. J Neurol. (2016 ) 263:1280–5.
Not in our library10.1007/s00415-016-8093-4 (opens in a new tab)
32.
Mody N Agouni A McIlroy GD Platt B Delibegovic M. Susceptibility to diet-induced obesity and glucose intolerance in the APP (SWE)/PSEN1 (A246E) mouse model of Alzheimer's disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein. Diabetologia (2011 ) 54:2143–51.
Not in our library10.1007/s00125-011-2160-2 (opens in a new tab)
33.
Ruiz HH Chi T Shin AC Lindtner C Hsieh W Ehrlich M. Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. Alzheimer's Dement. (2016 ) 12:851–61.
Not in our library10.1016/j.jalz.2016.01.008 (opens in a new tab)
34.
Jimenez-Palomares M Ramos-Rodriguez JJ Lopez-Acosta JF Pacheco-Herrero M Lechuga-Sancho AM Perdomo G. Increased Abeta production prompts the onset of glucose intolerance and insulin resistance. Am J Physiol Endocrinol Metab. (2012 ) 302:E1373–80.
Not in our library10.1152/ajpendo.00500.2011 (opens in a new tab)
35.
Takeda S Sato N Uchio-Yamada K Sawada K Kunieda T Takeuchi D. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci USA. (2010 ) 107:7036–41.
Not in our library10.1073/pnas.1000645107 (opens in a new tab)
36.
DiTacchio KA Heinemann SF Dziewczapolski G. Metformin treatment alters memory function in a mouse model of Alzheimer's disease. J Alzheimer's Dis. (2015 ) 44:43–8.
Not in our library10.3233/jad-141332 (opens in a new tab)
37.
Barini E Antico O Zhao Y Asta F Tucci V Catelani T. Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy. Mol Neurodegener. (2016 ) 11:16.
Not in our library10.1186/s13024-016-0082-7 (opens in a new tab)
38.
Interplay Between the Gut-Brain Axis, Obesity and Cognitive Function · 2018
No notice
39.
Li ZG Zhang W Sima AA. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes (2007 ) 56:1817–24.
Not in our library10.2337/db07-0171 (opens in a new tab)
40.
Pedersen WA McMillan PJ Kulstad JJ Leverenz JB Craft S Haynatzki GR. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol. (2006 ) 199:265–73.
Not in our library10.1016/j.expneurol.2006.01.018 (opens in a new tab)
41.
De Felice FG Vieira MN Bomfim TR Decker H Velasco PT Lambert MP. Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA. (2009 ) 106:1971–6.
Not in our library10.1073/pnas.0809158106 (opens in a new tab)
42.
Piriz J Muller A Trejo JL Torres-Aleman I. IGF-I and the aging mammalian brain. Exp Gerontol. (2011 ) 46:96–9.
Not in our library10.1016/j.exger.2010.08.022 (opens in a new tab)
43.
Salcedo I Tweedie D Li Y Greig NH. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br J Pharmacol. (2012 ) 166:1586–99.
Not in our library10.1111/j.1476-5381.2012.01971.x (opens in a new tab)
44.
Mattson MP Longo VD Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. (2017 ) 39:46–58.
Not in our library10.1016/j.arr.2016.10.005 (opens in a new tab)
45.
Bayliss JA Lemus MB Santos VV Deo M Davies JS Kemp BE. Metformin prevents nigrostriatal dopamine degeneration independent of AMPK activation in dopamine neurons. PLoS ONE (2016 ) 11:e0159381.
Not in our library10.1371/journal.pone.0159381 (opens in a new tab)
46.
Ismaiel AA Espinosa-Oliva AM Santiago M Garcia-Quintanilla A Oliva-Martin MJ Herrera AJ. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system. Toxicol Appl Pharmacol. (2016 ) 298:19–30.
Not in our library10.1016/j.taap.2016.03.004 (opens in a new tab)
47.
Kang H Khang R Ham S Jeong GR Kim H Jo M. Activation of the ATF2/CREB-PGC-1alpha pathway by metformin leads to dopaminergic neuroprotection. Oncotarget (2017 ) 8:48603–18.
Not in our library10.18632/oncotarget.18122 (opens in a new tab)
48.
Katila N Bhurtel S Shadfar S Srivastav S Neupane S Ojha U. Metformin lowers alpha-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson's disease. Neuropharmacology (2017 ) 125:396–407.
Not in our library10.1016/j.neuropharm.2017.08.015 (opens in a new tab)
49.
Lu M Su C Qiao C Bian Y Ding J Hu G. Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of parkinson's disease via autophagy and mitochondrial ROS clearance. Int J Neuropsychopharmacol. (2016 ) 19:pyw047.
Not in our library10.1093/ijnp/pyw047 (opens in a new tab)
50.
Patil SP Jain PD Ghumatkar PJ Tambe R Sathaye S. Neuroprotective effect of metformin in MPTP-induced Parkinson's disease in mice. Neuroscience (2014 ) 277:747–54.
Not in our library10.1016/j.neuroscience.2014.07.046 (opens in a new tab)
51.
Perez-Revuelta BI Hettich MM Ciociaro A Rotermund C Kahle PJ Krauss S. Metformin lowers Ser-129 phosphorylated alpha-synuclein levels via mTOR-dependent protein phosphatase 2A activation. Cell Death Dis. (2014 ) 5:e1209.
Not in our library10.1038/cddis.2014.175 (opens in a new tab)
52.
Porceddu PF Ishola IO Contu L Morelli M. Metformin prevented dopaminergic neurotoxicity induced by 3,4-Methylenedioxymethamphetamine administration. Neurotox Res. (2016 ) 30:101–9.
Not in our library10.1007/s12640-016-9633-5 (opens in a new tab)
53.
Chen F Dong RR Zhong KL Ghosh A Tang SS Long Y. Antidiabetic drugs restore abnormal transport of amyloid-beta across the blood-brain barrier and memory impairment in db/db mice. Neuropharmacology (2016 ) 101:123–36.
Not in our library10.1016/j.neuropharm.2015.07.023 (opens in a new tab)
54.
Kickstein E Krauss S Thornhill P Rutschow D Zeller R Sharkey J. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci USA. (2010 ) 107:21830–5.
Not in our library10.1073/pnas.0912793107 (opens in a new tab)
55.
Li J Deng J Sheng W Zuo Z. Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol Biochem Behav. (2012 ) 101:564–74.
Not in our library10.1016/j.pbb.2012.03.002 (opens in a new tab)
56.
Picone P Nuzzo D Caruana L Messina E Barera A Vasto S. Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-kappaB activation: use of insulin to attenuate metformin's effect. Biochim Biophys Acta (2015 ) 1853:1046–59.
Not in our library10.1016/j.bbamcr.2015.01.017 (opens in a new tab)
57.
Allard JS Perez EJ Fukui K Carpenter P Ingram DK de Cabo R. Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice. Behav Brain Res. (2016 ) 301:1–9.
Not in our library10.1016/j.bbr.2015.12.012 (opens in a new tab)
58.
Lennox R Porter DW Flatt PR Holscher C Irwin N Gault VA. Comparison of the independent and combined effects of sub-chronic therapy with metformin and a stable GLP-1 receptor agonist on cognitive function, hippocampal synaptic plasticity and metabolic control in high-fat fed mice. Neuropharmacology (2014 ) 86:22–30.
Not in our library10.1016/j.neuropharm.2014.06.026 (opens in a new tab)
59.
McNeilly AD Williamson R Balfour DJ Stewart CA Sutherland C A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin. Diabetologia (2012 ) 55:3061–70.
Not in our library10.1007/s00125-012-2686-y (opens in a new tab)
60.
Pintana H Apaijai N Pratchayasakul W Chattipakorn N Chattipakorn SC. Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci. (2012 ) 91:409–14.
Not in our library10.1016/j.lfs.2012.08.017 (opens in a new tab)
61.
Thangthaeng N Rutledge M Wong JM Vann PH Forster MJ Sumien N. Metformin impairs spatial memory and visual acuity in old male mice. Aging Dis. (2017 ) 8:17–30.
Not in our library10.14336/ad.2016.1010 (opens in a new tab)
62.
Ma TC Buescher JL Oatis B Funk JA Nash AJ Carrier RL. Metformin therapy in a transgenic mouse model of Huntington's disease. Neurosci Lett. (2007 ) 411:98–103.
Not in our library10.1016/j.neulet.2006.10.039 (opens in a new tab)
63.
Kaneb HM Sharp PS Rahmani-Kondori N Wells DJ. Metformin treatment has no beneficial effect in a dose-response survival study in the SOD1(G93A) mouse model of ALS and is harmful in female mice. PLoS ONE (2011 ) 6:e24189.
Not in our library10.1371/journal.pone.0024189 (opens in a new tab)
64.
Monette MC Baird A Jackson DL. A meta-analysis of cognitive functioning in nondemented adults with type 2 diabetes mellitus. Can J Diab. (2014 ) 38:401–8.
Not in our library10.1016/j.jcjd.2014.01.014 (opens in a new tab)
65.
Palta P Schneider AL Biessels GJ Touradji P Hill-Briggs F. Magnitude of cognitive dysfunction in adults with type 2 diabetes: a meta-analysis of six cognitive domains and the most frequently reported neuropsychological tests within domains. J Int Neuropsychol Soc. (2014 ) 20:278–91.
Not in our library10.1017/s1355617713001483 (opens in a new tab)
66.
Vincent C Hall PA. Executive function in adults with type 2 diabetes: a meta-analytic review. Psychosom Med. (2015 ) 77:631–42.
Not in our library10.1097/psy.0000000000000103 (opens in a new tab)
67.
Cooper C Sommerlad A Lyketsos CG Livingston G. Modifiable predictors of dementia in mild cognitive impairment: a systematic review and meta-analysis. Am J Psychiatry (2015 ) 172:323–34.
Not in our library10.1176/appi.ajp.2014.14070878 (opens in a new tab)
68.
Moulton CD Costafreda SG Horton P Ismail K Fu CH. Meta-analyses of structural regional cerebral effects in type 1 and type 2 diabetes. Brain Imaging Behav. (2015 ) 9:651–62.
Not in our library10.1007/s11682-014-9348-2 (opens in a new tab)
69.
Wu G Lin L Zhang Q Wu J. Brain gray matter changes in type 2 diabetes mellitus: a meta-analysis of whole-brain voxel-based morphometry study. J Diabetes Complicat. (2017 ). 31:1698–703.
Not in our library10.1016/j.jdiacomp.2017.09.001 (opens in a new tab)
70.
Diabetes and the Risk of Multi-System Aging Phenotypes: A Systematic Review and Meta-Analysis · 2009
No notice
71.
Profenno LA Porsteinsson AP Faraone SV. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry (2010 ) 67:505–12.
Not in our library10.1016/j.biopsych.2009.02.013 (opens in a new tab)
72.
Vagelatos NT Eslick GD. Type 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol Rev. (2013 ) 35:152–60.
Not in our library10.1093/epirev/mxs012 (opens in a new tab)
73.
Cheng G Huang C Deng H Wang H. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J. (2012 ) 42:484–91.
Not in our library10.1111/j.1445-5994.2012.02758.x (opens in a new tab)
74.
Janson J Laedtke T Parisi JE O'Brien P Petersen RC Butler PC. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes (2004 ) 53:474–81.
Not in our library10.2337/diabetes.53.2.474 (opens in a new tab)
75.
Matsuzaki T Sasaki K Tanizaki Y Hata J Fujimi K Matsui Y. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology (2010 ) 75:764–70.
Not in our library10.1212/wnl.0b013e3181eee25f (opens in a new tab)
76.
Turner R Craft S Aisen P Individuals with Alzheimer's disease exhibit a high prevalence of undiagnosed impaired glucose tolerance and type 2 diabetes mellitus. Alzheimer's Dement. (2013 ) 9:P284–5.
Not in our library10.1016/j.jalz.2013.05.573 (opens in a new tab)
77.
Frolich L Blum-Degen D Riederer P Hoyer S. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease. Ann NY Acad Sci. (1999 ) 893:290–3.
Not in our library10.1111/j.1749-6632.1999.tb07839.x (opens in a new tab)
78.
Rivera EJ Goldin A Fulmer N Tavares R Wands JR de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimer's Dis. (2005 ) 8:247–68.
Not in our library10.3233/jad-2005-8304 (opens in a new tab)
79.
Bomfim TR Forny-Germano L Sathler LB Brito-Moreira J Houzel JC Decker H. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Abeta oligomers. J Clin Invest. (2012 ) 122:1339–53.
Not in our library10.1172/jci57256 (opens in a new tab)
80.
Talbot K Wang HY Kazi H Han LY Bakshi KP Stucky A. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. (2012 ) 122:1316–38.
Not in our library10.1172/jci59903 (opens in a new tab)
81.
Luchsinger JA Tang MX Shea S Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology (2004 ) 63:1187–92.
Not in our library10.1212/01.wnl.0000140292.04932.87 (opens in a new tab)
82.
Baker LD Cross DJ Minoshima S Belongia D Watson GS Craft S Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol. (2011 ) 68:51–7.
Not in our library10.1001/archneurol.2010.225 (opens in a new tab)
83.
Arvanitakis Z Schneider JA Wilson RS Li Y Arnold SE Wang Z Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology (2006 ) 67:1960–5.
Not in our library10.1212/01.wnl.0000247053.45483.4e (opens in a new tab)
84.
Abner EL Nelson PT Kryscio RJ Schmitt FA Fardo DW Woltjer RL Diabetes is associated with cerebrovascular but not Alzheimer's disease neuropathology. Alzheimer's Dement. (2016 ) 12:882–9.
Not in our library10.1016/j.jalz.2015.12.006 (opens in a new tab)
85.
Crane PK Walker RL Sonnen J Gibbons LE Melrose R Hassenstab J. Glucose levels during life and neuropathologic findings at autopsy among people never treated for diabetes. Neurobiol Aging (2016 ) 48:72–82.
Not in our library10.1016/j.neurobiolaging.2016.07.021 (opens in a new tab)
86.
Dos Santos Matioli MNP Suemoto CK Rodriguez RD Farias DS da Silva MM Leite REP Diabetes is not associated with Alzheimer's disease neuropathology. J Alzheimer's Dis. (2017 ) 60:1035–43.
Not in our library10.3233/jad-170179 (opens in a new tab)
87.
Pruzin JJ Schneider JA Capuano AW Leurgans SE Barnes LL Ahima RS. Diabetes, hemoglobin A1C, and regional Alzheimer disease and infarct pathology. Alzheimer Dis Assoc Disord. (2017 ) 31:41–7.
Not in our library10.1097/wad.0000000000000172 (opens in a new tab)
88.
Beeri MS Silverman JM Davis KL Marin D Grossman HZ Schmeidler J. Type 2 diabetes is negatively associated with Alzheimer's disease neuropathology. J Gerontol Ser A Biol Sci Med Sci. (2005 ) 60:471–5.
Not in our library10.1093/gerona/60.4.471 (opens in a new tab)
89.
Ahtiluoto S Polvikoski T Peltonen M Solomon A Tuomilehto J Winblad B. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology (2010 ) 75:1195–202.
Not in our library10.1212/wnl.0b013e3181f4d7f8 (opens in a new tab)
90.
Prevalence of mixed pathologies in the aging brain · 2014
No notice
91.
Norton S Matthews FE Barnes DE Yaffe K Brayne C. Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. (2014 ) 13:788–94.
Not in our library10.1016/s1474-4422(14)70136-x (opens in a new tab)
92.
Wahlqvist ML Lee MS Hsu CC Chuang SY Lee JT Tsai HN. Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson's disease occurring with Type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat Disord. (2012 ) 18:753–8.
Not in our library10.1016/j.parkreldis.2012.03.010 (opens in a new tab)
93.
Brakedal B Flønes I Reiter SF Torkildsen Ø Dölle C Assmus J. Glitazone use associated with reduced risk of Parkinson's disease. Mov Dis (2017 ) 32:1594–9.
Not in our library10.1002/mds.27128 (opens in a new tab)
94.
Brakedal B Haugarvoll K Tzoulis C. Simvastatin is associated with decreased risk of Parkinson disease. Ann Neurol. (2017 ) 81:329–30.
Not in our library10.1002/ana.24857 (opens in a new tab)
95.
Kuan YC Huang KW Lin CL Hu CJ Kao CH. Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psychiatry (2017 ) 79:77–83.
Not in our library10.1016/j.pnpbp.2017.06.002 (opens in a new tab)
96.
Hsu CC Wahlqvist ML Lee MS Tsai HN. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimer's Dis. (2011 ) 24:485–93.
Not in our library10.3233/jad-2011-101524 (opens in a new tab)
97.
Cheng C Lin CH Tsai YW Tsai CJ Chou PH Lan TH. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol Ser A Biol Sci Med Sci (2014 ) 69:1299–305.
Not in our library10.1093/gerona/glu073 (opens in a new tab)
98.
Heneka MT Fink A Doblhammer G. Effect of pioglitazone medication on the incidence of dementia. Ann Neurol. (2015 ) 78:284–94.
Not in our library10.1002/ana.24439 (opens in a new tab)
99.
Ye F Luo YJ Xiao J Yu NW Yi G. Impact of insulin sensitizers on the incidence of dementia: a meta-analysis. Dement Geriatr Cogn Disord. (2016 ) 41:251–60.
Not in our library10.1159/000445941 (opens in a new tab)
100.
Wang CP Lorenzo C Habib SL Jo B Espinoza SE. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J Diabetes Complicat. (2017 ) 31:679–86.
Not in our library10.1016/j.jdiacomp.2017.01.013 (opens in a new tab)
101.
Orkaby AR Cho K Cormack J Gagnon DR Driver JA. Metformin vs sulfonylurea use and risk of dementia in US veterans aged >/ = 65 years with diabetes. Neurology (2017 ) 89:1877–85.
Not in our library10.1212/wnl.0000000000004586 (opens in a new tab)
102.
Ng TP Feng L Yap KB Lee TS Tan CH Winblad B. Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimer's Dis. (2014 ) 41:61–8.
Not in our library10.3233/jad-131901 (opens in a new tab)
103.
Imfeld P Bodmer M Jick SS Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. J Am Geriatr Soc. (2012 ) 60:916–21.
Not in our library10.1111/j.1532-5415.2012.03916.x (opens in a new tab)
104.
Diabetes Mellitus and the Risk of Alzheimer’s Disease: A Nationwide Population-Based Study · 2014
No notice
105.
Koenig AM Mechanic-Hamilton D Xie SX Combs MF Cappola AR Xie L. Effects of the insulin sensitizer metformin in Alzheimer Disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord. (2017 ) 31:107–13.
Not in our library10.1097/wad.0000000000000202 (opens in a new tab)
106.
Hervas D Fornes-Ferrer V Gomez-Escribano AP Sequedo MD Peiro C Millan JM. Metformin intake associates with better cognitive function in patients with Huntington's disease. PLoS ONE (2017 ) 12:e0179283.
Not in our library10.1371/journal.pone.0179283 (opens in a new tab)
107.
Yokoyama H Ogawa M Honjo J Okizaki S Yamada D Shudo R Risk factors associated with abnormal cognition in Japanese outpatients with diabetes, hypertension or dyslipidemia. Diabetol Int. (2015 ) 6:268–74.
Not in our library10.1007/s13340-014-0194-7 (opens in a new tab)
108.
Luchsinger JA Perez T Chang H Mehta P Steffener J Pradabhan G. Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial. J Alzheimer's Dis. (2016 ) 51:501–14.
Not in our library10.3233/jad-150493 (opens in a new tab)
109.
de Lau LM Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. (2006 ) 5:525–35.
Not in our library10.1016/s1474-4422(06)70471-9 (opens in a new tab)
110.
Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatr. (2008 ) 79:368–76.
Not in our library10.1136/jnnp.2007.131045 (opens in a new tab)
111.
Damier P Hirsch EC Agid Y Graybiel AM The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain (1999 ) 122(Pt 8), 1437–48.
Not in our library10.1093/brain/122.8.1437 (opens in a new tab)
112.
Schneider SA Obeso JA. Clinical and pathological features of Parkinson's disease. Curr Top Behav Neurosci. (2014 ) 22:205–20.
Not in our library10.1007/7854_2014_317 (opens in a new tab)
113.
Spillantini MG Schmidt ML Lee VM Trojanowski JQ Jakes R Goedert M. Alpha-synuclein in Lewy bodies. Nature (1997 ) 388:839–40.
Not in our library10.1038/42166 (opens in a new tab)
114.
Braak H Del Tredici K Bratzke H Hamm-Clement J Sandmann-Keil D Rub U. Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J Neurol. (2002 ) 249(Suppl. 3):iii1–5.
Not in our library10.1007/s00415-002-1301-4 (opens in a new tab)
115.
Beach TG Adler CH Lue L Sue LI Bachalakuri J Henry-Watson J. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. (2009 ) 117:613–34.
Not in our library10.1007/s00401-009-0538-8 (opens in a new tab)
116.
Gasser T. Identifying PD-causing genes and genetic susceptibility factors: current approaches and future prospects. Prog Brain Res. (2010 ) 183:3–20.
Not in our library10.1016/s0079-6123(10)83001-8 (opens in a new tab)
117.
Deng H Wang P Jankovic J. The genetics of Parkinson disease. Ageing Res Rev. (2017 ) 42:72–85.
Not in our library10.1016/j.arr.2017.12.007 (opens in a new tab)
118.
Klein C Westenberger A. Genetics of Parkinson's disease. Cold Spring Harb Perspect Med. (2012 ) 2:a008888.
Not in our library10.1101/cshperspect.a008888 (opens in a new tab)
119.
Dunn L Allen GF Mamais A Ling H Li A Duberley KE. Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease. Neurobiol Aging (2014 ) 35:1111–5.
Not in our library10.1016/j.neurobiolaging.2013.11.001 (opens in a new tab)
120.
Athauda D Foltynie T. The ongoing pursuit of neuroprotective therapies in Parkinson disease. Nat Rev Neurol. (2015 ) 11:25–40.
Not in our library10.1038/nrneurol.2014.226 (opens in a new tab)
121.
Choi JY Jang EH Park CS Kang JH. Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity. Free Radic Biol Med. (2005 ) 38:806–16.
Not in our library10.1016/j.freeradbiomed.2004.12.008 (opens in a new tab)
122.
Morris JK Bomhoff GL Stanford JA Geiger PC. Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet. Am J Physiol Regul Integr Compar Physiol. (2010 ) 299:R1082–90.
Not in our library10.1152/ajpregu.00449.2010 (opens in a new tab)
123.
Rotermund C Truckenmuller FM Schell H Kahle PJ. Diet-induced obesity accelerates the onset of terminal phenotypes in alpha-synuclein transgenic mice. J Neurochem. (2014 ) 131:848–58.
Not in our library10.1111/jnc.12813 (opens in a new tab)
124.
Morris JK Bomhoff GL Gorres BK Davis VA Kim J Lee PP. Insulin resistance impairs nigrostriatal dopamine function. Exp Neurol. (2011 ) 231:171–80.
Not in our library10.1016/j.expneurol.2011.06.005 (opens in a new tab)
125.
Wang L Zhai YQ Xu LL Qiao C Sun XL Ding JH. Metabolic inflammation exacerbates dopaminergic neuronal degeneration in response to acute MPTP challenge in type 2 diabetes mice. Exp Neurol. (2014 ) 251:22–9.
Not in our library10.1016/j.expneurol.2013.11.001 (opens in a new tab)
126.
Hu G Jousilahti P Bidel S Antikainen R Tuomilehto J. Type 2 diabetes and the risk of Parkinson's disease. Diabetes Care (2007 ) 30:842–7.
Not in our library10.2337/dc06-2011 (opens in a new tab)
127.
Simon KC Chen H Schwarzschild M Ascherio A. Hypertension, hypercholesterolemia, diabetes, and risk of Parkinson disease. Neurology (2007 ) 69:1688–95.
Not in our library10.1212/01.wnl.0000271883.45010.8a (opens in a new tab)
128.
Driver JA Smith A Buring JE Gaziano JM Kurth T Logroscino G. Prospective cohort study of type 2 diabetes and the risk of Parkinson's disease. Diabetes Care (2008 ) 31:2003–5.
Not in our library10.2337/dc08-0688 (opens in a new tab)
129.
D'Amelio M Ragonese P Callari G Di Benedetto N Palmeri B Terruso V. Diabetes preceding Parkinson's disease onset. A case-control study. Parkinsonism Relat Disord. (2009 ) 15:660–4.
Not in our library10.1016/j.parkreldis.2009.02.013 (opens in a new tab)
130.
Miyake Y Tanaka K Fukushima W Sasaki S Kiyohara C Tsuboi Y. Case-control study of risk of Parkinson's disease in relation to hypertension, hypercholesterolemia, and diabetes in Japan. J Neurol Sci. (2010 ) 293:82–6.
Not in our library10.1016/j.jns.2010.03.002 (opens in a new tab)
131.
Schernhammer E Hansen J Rugbjerg K Wermuth L Ritz B. Diabetes and the risk of developing Parkinson's disease in Denmark. Diabetes Care (2011 ) 34:1102–8.
Not in our library10.2337/dc10-1333 (opens in a new tab)
132.
Xu Q Park Y Huang X Hollenbeck A Blair A Schatzkin A. Diabetes and risk of Parkinson's disease. Diabetes Care (2011 ) 34:910–5.
Not in our library10.2337/dc10-1922 (opens in a new tab)
133.
Diabetes and risk of Parkinson's disease: an updated meta-analysis of case-control studies. · 2014
Not checked
134.
Cereda E Barichella M Pedrolli C Klersy C Cassani E Caccialanza R. Diabetes and risk of Parkinson's disease: a systematic review and meta-analysis. Diabetes Care (2011 ) 34:2614–23.
Not in our library10.2337/dc11-1584 (opens in a new tab)
135.
Yue X Li H Yan H Zhang P Chang L Li T. Risk of Parkinson disease in diabetes mellitus: an updated meta-analysis of population-based cohort studies. Medicine (2016 ) 95:e3549.
Not in our library10.1097/md.0000000000003549 (opens in a new tab)
136.
Crane PK Walker R Hubbard RA Li G Nathan DM Zheng H Glucose levels and risk of dementia. N Engl J Med. (2013 ) 369:540–8.
Not in our library10.1056/nejmoa1215740 (opens in a new tab)
137.
Walker Z Possin KL Boeve BF Aarsland D. Lewy body dementias. Lancet (2015 ) 386:1683–97.
Not in our library10.1016/s0140-6736(15)00462-6 (opens in a new tab)
138.
Ong M Foo H Chander RJ Wen MC Au WL Sitoh YY. Influence of diabetes mellitus on longitudinal atrophy and cognition in Parkinson's disease. J Neurol Sci. (2017 ) 377:122–6.
Not in our library10.1016/j.jns.2017.04.010 (opens in a new tab)
139.
Bosco D Plastino M Cristiano D Colica C Ermio C De Bartolo M. Dementia is associated with insulin resistance in patients with Parkinson's disease. J Neurol Sci. (2012 ) 315:39–43.
Not in our library10.1016/j.jns.2011.12.008 (opens in a new tab)
140.
Secnik J Cermakova P Fereshtehnejad SM Dannberg P Johnell K Fastbom J. Diabetes in a large dementia cohort: clinical characteristics and treatment from the Swedish dementia registry. Diabetes Care (2017 ) 40:1159–66.
Not in our library10.2337/dc16-2516 (opens in a new tab)
141.
Levy G Tang MX Cote LJ Louis ED Alfaro B Mejia H. Do risk factors for Alzheimer's disease predict dementia in Parkinson's disease? An exploratory study. Mov Disord. (2002 ) 17:250–7.
Not in our library10.1002/mds.10086 (opens in a new tab)
142.
Vascular disease and vascular risk factors in relation to motor features and cognition in early Parkinson's disease · 2016
No notice
143.
Pilotto A Turrone R Liepelt-Scarfone I Bianchi M Poli L Borroni B. Vascular risk factors and cognition in Parkinson's disease. J Alzheimer's Dis. (2016 ) 51:563–70.
Not in our library10.3233/jad-150610 (opens in a new tab)
144.
Xu Y Yang J Shang H. Meta-analysis of risk factors for Parkinson's disease dementia. Transl Neurodegener. (2016 ) 5:11.
Not in our library10.1186/s40035-016-0058-0 (opens in a new tab)
145.
Malfitano AM Marasco G Proto MC Laezza C Gazzerro P Bifulco M. Statins in neurological disorders: an overview and update. Pharmacol Res. (2014 ) 88:74–83.
Not in our library10.1016/j.phrs.2014.06.007 (opens in a new tab)
146.
Abe K Aoki M Tsuji S Itoyama Y Sobue G Togo M Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. (2017 ) 16:505–12.
Not in our library10.1016/s1474-4422(17)30115-1 (opens in a new tab)
147.
Mullard A 2017 FDA drug approvals. Nat Rev Drug Discov. (2018 ) 17:81
Not in our library10.1038/nrd.2018.4 (opens in a new tab)
148.
Kioumourtzoglou MA Rotem RS Seals RM Gredal O Hansen J Weisskopf MG. Diabetes mellitus, obesity, and diagnosis of amyotrophic lateral sclerosis: a population-based study. JAMA Neurol. (2015 ) 72:905–11.
Not in our library10.1001/jamaneurol.2015.0910 (opens in a new tab)
149.
Mariosa D Kamel F Bellocco R Ye W Fang F. Association between diabetes and amyotrophic lateral sclerosis in Sweden. Eur J Neurol. (2015 ) 22:1436–42.
Not in our library10.1111/ene.12632 (opens in a new tab)
150.
Jawaid A Salamone AR Strutt AM Murthy SB Wheaton M McDowell EJ. ALS disease onset may occur later in patients with pre-morbid diabetes mellitus. Eur J Neurol. (2010 ) 17:733–9.
Not in our library10.1111/j.1468-1331.2009.02923.x (opens in a new tab)
151.
D'Ovidio F d'Errico A Carna P Calvo A Costa G Chio A. The role of pre-morbid diabetes on developing amyotrophic lateral sclerosis. Eur J Neurol. (2018 ) 25:164–70.
Not in our library10.1111/ene.13465 (opens in a new tab)
152.
Paganoni S Hyman T Shui A Allred P Harms M Liu J Pre-morbid type 2 diabetes mellitus is not a prognostic factor in amyotrophic lateral sclerosis. Muscle Nerve (2015 ) 52:339–43.
Not in our library10.1002/mus.24688 (opens in a new tab)
153.
Sun Y Lu CJ Chen RC Hou WH Li CY. Risk of amyotrophic lateral sclerosis in patients with diabetes: a nationwide population-based cohort study. J Epidemiol. (2015 ) 25:445–51.
Not in our library10.2188/jea.je20140176 (opens in a new tab)
154.
Hollinger SK Okosun IS Mitchell CS. Antecedent disease and amyotrophic lateral sclerosis: what is protecting whom? Front Neurol. (2016 ) 7:47.
Not in our library10.3389/fneur.2016.00047 (opens in a new tab)
155.
Park Y Park J Kim Y Baek H Kim SH. Association between nutritional status and disease severity using the amyotrophic lateral sclerosis (ALS) functional rating scale in ALS patients. Nutrition (2015 ) 31:1362–7.
Not in our library10.1016/j.nut.2015.05.025 (opens in a new tab)
156.
A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis · 2012
No notice
157.
Wills AM Hubbard J Macklin EA Glass J Tandan R Simpson EP. Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet (2014 ) 383:2065–72.
Not in our library10.1016/s0140-6736(14)60222-1 (opens in a new tab)
158.
Levine TD Bowser R Hank NC Gately S Stephan D Saperstein DS. A pilot trial of pioglitazone HCl and tretinoin in ALS: cerebrospinal fluid biomarkers to monitor drug efficacy and predict rate of disease progression. Neurol Res Int. (2012 ) 2012:582075.
Not in our library10.1155/2012/582075 (opens in a new tab)
159.
Lalic NM Maric J Svetel M Jotic A Stefanova E Lalic K. Glucose homeostasis in Huntington disease: abnormalities in insulin sensitivity and early-phase insulin secretion. Arch Neurol. (2008 ) 65:476–80.
Not in our library10.1001/archneur.65.4.476 (opens in a new tab)
160.
Montojo MT Aganzo M Gonzalez N. Huntington's disease and diabetes: chronological sequence of its association. J Huntington's Dis. (2017 ) 6:179–88.
Not in our library10.3233/jhd-170253 (opens in a new tab)
161.
Hu Y Liang J Yu S. High prevalence of diabetes mellitus in a five-generation Chinese family with Huntington's disease. J Alzheimer's Dis. (2014 ) 40:863–8.
Not in our library10.3233/jad-131847 (opens in a new tab)
162.
Boesgaard TW Nielsen TT Josefsen K Hansen T Jorgensen T Pedersen O Huntington's disease does not appear to increase the risk of diabetes mellitus. J Neuroendocrinol. (2009 ) 21:770–6.
Not in our library10.1111/j.1365-2826.2009.01898.x (opens in a new tab)
163.
Russo CV Salvatore E Sacca F Tucci T Rinaldi C Sorrentino P. Insulin sensitivity and early-phase insulin secretion in normoglycemic Huntington's disease patients. J Huntington's Dis. (2013 ) 2:501–7.
Not in our library10.3233/jhd-130078 (opens in a new tab)
164.
Sriwijitkamol A Coletta DK Wajcberg E Balbontin GB Reyna SM Barrientes J. Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study. Diabetes (2007 ) 56:836–48.
Not in our library10.2337/db06-1119 (opens in a new tab)
165.
Xu XJ Gauthier MS Hess DT Apovian CM Cacicedo JM Gokce N. Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue. J Lipid Res. (2012 ) 53:792–801.
Not in our library10.1194/jlr.p022905 (opens in a new tab)
166.
Culmsee C Monnig J Kemp BE Mattson MP. AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci. (2001 ) 17:45–58.
Not in our library10.1385/jmn:17:1:45 (opens in a new tab)
167.
Garcia-Gil M Pesi R Perna S Allegrini S Giannecchini M Camici M. 5'-aminoimidazole-4-carboxamide riboside induces apoptosis in human neuroblastoma cells. Neuroscience (2003 ) 117:811–20.
Not in our library10.1016/s0306-4522(02)00836-9 (opens in a new tab)
168.
Meares GP Qin H Liu Y Holdbrooks AT Benveniste EN. AMP-activated protein kinase restricts IFN-gamma signaling. J Immunol. (2013 ) 190:372–80.
Not in our library10.4049/jimmunol.1202390 (opens in a new tab)
169.
Greco SJ Sarkar S Johnston JM Tezapsidis N. Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochem Biophys Res Commun. (2009 ) 380:98–104.
Not in our library10.1016/j.bbrc.2009.01.041 (opens in a new tab)
170.
Vingtdeux V Giliberto L Zhao H Chandakkar P Wu Q Simon JE. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. J Biol Chem. (2010 ) 285:9100–13.
Not in our library10.1074/jbc.m109.060061 (opens in a new tab)
171.
Thornton C Bright NJ Sastre M Muckett PJ Carling D. AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid beta-peptide exposure. Biochem J. (2011 ) 434:503–12.
Not in our library10.1042/bj20101485 (opens in a new tab)
172.
Mairet-Coello G Courchet J Pieraut S Courchet V Maximov A Polleux F. The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Abeta oligomers through Tau phosphorylation. Neuron (2013 ) 78:94–108.
Not in our library10.1016/j.neuron.2013.02.003 (opens in a new tab)
173.
Maziere JC Maziere C Mora L Gardette J Salmon S Auclair M. The antidiabetic drug metformin decreases cholesterol metabolism in cultured human fibroblasts. Atherosclerosis (1988 ) 71:27–33.
Not in our library10.1016/0021-9150(88)90299-7 (opens in a new tab)
174.
Shaw RJ Lamia KA Vasquez D Koo SH Bardeesy N DePinho RA. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science (2005 ) 310:1642–6.
Not in our library10.1126/science.1120781 (opens in a new tab)
175.
Stephenne X Foretz M Taleux N van der Zon GC Sokal E Hue L. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia (2011 ) 54:3101–10.
Not in our library10.1007/s00125-011-2311-5 (opens in a new tab)
176.
Chiang MC Cheng YC Chen SJ Yen CH Huang RN. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction. Exp Cell Res. (2016 ) 347:322–31.
Not in our library10.1016/j.yexcr.2016.08.013 (opens in a new tab)
177.
Gupta A Bisht B Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes. Neuropharmacology (2011 ) 60:910–20.
Not in our library10.1016/j.neuropharm.2011.01.033 (opens in a new tab)
178.
Hettich MM Matthes F Ryan DP Griesche N Schroder S Dorn S. The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex. PLoS ONE (2014 ) 9:e102420.
Not in our library10.1371/journal.pone.0102420 (opens in a new tab)
179.
Chen Y Zhou K Wang R Liu Y Kwak YD Ma T. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci USA. (2009 ) 106:3907–12.
Not in our library10.1073/pnas.0807991106 (opens in a new tab)
180.
Choi JS Park C Jeong JW. AMP-activated protein kinase is activated in Parkinson's disease models mediated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Biochem Biophys Res Commun. (2010 ) 391:147–51.
Not in our library10.1016/j.bbrc.2009.11.022 (opens in a new tab)
181.
Ng CH Guan MS Koh C Ouyang X Yu F Tan EK. AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson's disease. J Neurosci. (2012 ) 32:14311–7.
Not in our library10.1523/jneurosci.0499-12.2012 (opens in a new tab)
182.
Dulovic M Jovanovic M Xilouri M Stefanis L Harhaji-Trajkovic L Kravic-Stevovic T. The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro. Neurobiol Dis. (2014 ) 63:1–11.
Not in our library10.1016/j.nbd.2013.11.002 (opens in a new tab)
183.
Bobela W Nazeeruddin S Knott G Aebischer P Schneider BL. Modulating the catalytic activity of AMPK has neuroprotective effects against alpha-synuclein toxicity. Mol Neurodegener. (2017 ) 12:80.
Not in our library10.1186/s13024-017-0220-x (opens in a new tab)
184.
Jiang P Gan M Ebrahim AS Castanedes-Casey M Dickson DW Yen SH. Adenosine monophosphate-activated protein kinase overactivation leads to accumulation of alpha-synuclein oligomers and decrease of neurites. Neurobiol Aging (2013 ) 34, 1504–15.
Not in our library10.1016/j.neurobiolaging.2012.11.001 (opens in a new tab)
185.
Duran-Aniotz C Hetz C. Glucose metabolism: a sweet relief of Alzheimer's disease. Curr Biol. (2016 ) 26:R806–9.
Not in our library10.1016/j.cub.2016.07.060 (opens in a new tab)
186.
Herrero-Mendez A Almeida A Fernandez E Maestre C Moncada S Bolanos JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol. (2009 ) 11:747–52.
Not in our library10.1038/ncb1881 (opens in a new tab)
187.
Lee Y Morrison BM Li Y Lengacher S Farah MH Hoffman PN. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature (2012 ) 487:443–8.
Not in our library10.1038/nature11314 (opens in a new tab)
188.
Funfschilling U Supplie LM Mahad D Boretius S Saab AS Edgar J. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature (2012 ) 485:517–21.
Not in our library10.1038/nature11007 (opens in a new tab)
189.
Bouzier-Sore AK Voisin P Canioni P Magistretti PJ Pellerin L. Lactate is a preferential oxidative energy substrate over glucose for neurons in culture. J Cereb Blood Flow Metab. (2003 ) 23:1298–306.
Not in our library10.1097/01.wcb.0000091761.61714.25 (opens in a new tab)
190.
Borghammer P. Perfusion and metabolism imaging studies in Parkinson's disease. Dan Med J. (2012 ) 59:B4466.
Not in our library
191.
Woods SC Lotter EC McKay LD Porte D Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature (1979 ) 282:503–5.
Not in our library10.1038/282503a0 (opens in a new tab)
192.
Obici S Zhang BB Karkanias G Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med. (2002 ) 8:1376–82.
Not in our library10.1038/nm1202-798 (opens in a new tab)
193.
Morton GJ Cummings DE Baskin DG Barsh GS Schwartz MW. Central nervous system control of food intake and body weight. Nature (2006 ) 443:289–95.
Not in our library10.1038/nature05026 (opens in a new tab)
194.
Lozovsky D Saller CF Kopin IJ. Dopamine receptor binding is increased in diabetic rats. Science (1981 ) 214:1031–3.
Not in our library10.1126/science.6458088 (opens in a new tab)
195.
Lozovsky DB Kopin IJ Saller CF. Modulation of dopamine receptor supersensitivity by chronic insulin: implication in schizophrenia. Brain Res. (1985 ) 343:190–3.
Not in our library10.1016/0006-8993(85)91178-3 (opens in a new tab)
196.
Danguir J Elghozi JL Laude D. Increased dopamine and serotonin metabolites in CSF during severe insulin-induced hypoglycemia in freely moving rats. Neurochem Int. (1984 ) 6:71–5.
Not in our library10.1016/0197-0186(84)90028-7 (opens in a new tab)
197.
Colin E Regulier E Perrin V Durr A Brice A Aebischer P. Akt is altered in an animal model of Huntington's disease and in patients. Eur J Neurosci. (2005 ) 21:1478–88.
Not in our library10.1111/j.1460-9568.2005.03985.x (opens in a new tab)
198.
Griffin RJ Moloney A Kelliher M Johnston JA Ravid R Dockery P. Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. J Neurochem. (2005 ) 93:105–17.
Not in our library10.1111/j.1471-4159.2004.02949.x (opens in a new tab)
199.
Malagelada C Jin ZH Greene LA. RTP801 is induced in Parkinson's disease and mediates neuron death by inhibiting Akt phosphorylation/activation. J Neurosci. (2008 ) 28:14363–71.
Not in our library10.1523/jneurosci.3928-08.2008 (opens in a new tab)
200.
Timmons S Coakley MF Moloney AM O' Neill C. Akt signal transduction dysfunction in Parkinson's disease. Neurosci Lett. (2009 ) 467:30–5.
Not in our library10.1016/j.neulet.2009.09.055 (opens in a new tab)
201.
Shepherd PR Withers DJ Siddle K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J. (1998 ) 333(Pt 3):471–90.
Not in our library10.1042/bj3330471 (opens in a new tab)
202.
Manning BD Cantley LC. AKT/PKB signaling: navigating downstream. Cell (2007 ) 129:1261–74.
Not in our library10.1016/j.cell.2007.06.009 (opens in a new tab)
203.
Andjelkovic M Alessi DR Meier R Fernandez A Lamb NJ Frech M. Role of translocation in the activation and function of protein kinase B. J Biol Chem. (1997 ) 272:31515–24.
Not in our library10.1074/jbc.272.50.31515 (opens in a new tab)
204.
Brognard J Sierecki E Gao T Newton AC. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell (2007 ) 25:917–31.
Not in our library10.1016/j.molcel.2007.02.017 (opens in a new tab)
205.
Stambolic V Suzuki A de la Pompa JL Brothers GM Mirtsos C Sasaki T. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell (1998 ) 95:29–39.
Not in our library10.1016/s0092-8674(00)81780-8 (opens in a new tab)
206.
Yamauchi T Tobe K Tamemoto H Ueki K Kaburagi Y Yamamoto-Honda R. Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol. (1996 ) 16:3074–84.
Not in our library10.1128/mcb.16.6.3074 (opens in a new tab)
207.
Bruning JC Michael MD Winnay JN Hayashi T Horsch D Accili D. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell (1998 ) 2:559–69.
Not in our library10.1016/s1097-2765(00)80155-0 (opens in a new tab)
208.
Previs SF Withers DJ Ren JM White MF Shulman GI. Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem. (2000 ) 275:38990–4.
Not in our library10.1074/jbc.m006490200 (opens in a new tab)
209.
Reger MA Watson GS Frey WH II Baker LD Cholerton B Keeling ML. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging (2006 ) 27:451–8.
Not in our library10.1016/j.neurobiolaging.2005.03.016 (opens in a new tab)
210.
McNay EC Ong CT McCrimmon RJ Cresswell J Bogan JS Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. (2010 ) 93:546–53.
Not in our library10.1016/j.nlm.2010.02.002 (opens in a new tab)
211.
Takadera T Sakura N Mohri T Hashimoto T. Toxic effect of a beta-amyloid peptide (beta 22-35) on the hippocampal neuron and its prevention. Neurosci Lett. (1993 ) 161:41–4.
Not in our library10.1016/0304-3940(93)90135-8 (opens in a new tab)
212.
Rensink AA Otte-Holler I de Boer R Bosch RR ten Donkelaar HJ de Waal RM. Insulin inhibits amyloid beta-induced cell death in cultured human brain pericytes. Neurobiol Aging (2004 ) 25:93–103.
Not in our library10.1016/s0197-4580(03)00039-3 (opens in a new tab)
213.
Di Carlo M Picone P Carrotta R Giacomazza D San Biagio PL. Insulin promotes survival of amyloid-beta oligomers neuroblastoma damaged cells via caspase 9 inhibition and Hsp70 upregulation. J Biomed Biotechnol. (2010 ) 2010:147835.
Not in our library10.1155/2010/147835 (opens in a new tab)
214.
Mirsky IA Broh-Kahn RH. The inactivation of insulin by tissue extracts; the distribution and properties of insulin inactivating extracts. Arch Biochem. (1949 ) 20:1–9.
Not in our library
215.
Vekrellis K Ye Z Qiu WQ Walsh D Hartley D Chesneau V. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci. (2000 ) 20:1657–65.
Not in our library10.1523/jneurosci.20-05-01657.2000 (opens in a new tab)
216.
Farris W Mansourian S Chang Y Lindsley L Eckman EA Frosch MP. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA. (2003 ) 100:4162–7.
Not in our library10.1073/pnas.0230450100 (opens in a new tab)
217.
Cook DG Leverenz JB McMillan PJ Kulstad JJ Ericksen S Roth RA. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol. (2003 ) 162:313–9.
Not in our library10.1016/s0002-9440(10)63822-9 (opens in a new tab)
218.
Ertekin-Taner N Allen M Fadale D Scanlin L Younkin L Petersen RC. Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. Hum Mutat. (2004 ) 23:334–42.
Not in our library10.1002/humu.20016 (opens in a new tab)
219.
Zuo X Jia J. Promoter polymorphisms which modulate insulin degrading enzyme expression may increase susceptibility to Alzheimer's disease. Brain Res. (2009 ) 1249:1–8.
Not in our library10.1016/j.brainres.2008.10.034 (opens in a new tab)
220.
Reitz C Cheng R Schupf N Lee JH Mehta PD Rogaeva E. Association between variants in IDE-KIF11-HHEX and plasma amyloid beta levels. Neurobiol Aging (2012 ) 33:199.e113–197.
Not in our library10.1016/j.neurobiolaging.2010.07.005 (opens in a new tab)
221.
Wang S He F Wang Y. Association between polymorphisms of the insulin-degrading enzyme gene and late-onset Alzheimer disease. J Geriatr Psychiatry Neurol. (2015 ) 28:94–8.
Not in our library10.1177/0891988714554707 (opens in a new tab)
222.
Kochkina EG Plesneva SA Vasilev DS Zhuravin IA Turner AJ Nalivaeva NN. Effects of ageing and experimental diabetes on insulin-degrading enzyme expression in male rat tissues. Biogerontology (2015 ) 16:473–84.
Not in our library10.1007/s10522-015-9569-9 (opens in a new tab)
223.
Barber AJ Nakamura M Wolpert EB Reiter CE Seigel GM Antonetti DA. Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3. J Biol Chem. (2001 ) 276:32814–21.
Not in our library10.1074/jbc.m104738200 (opens in a new tab)
224.
Duarte AI Santos MS Seica R de Oliveira CR. Insulin affects synaptosomal GABA and glutamate transport under oxidative stress conditions. Brain Res. (2003 ) 977:23–30.
Not in our library10.1016/s0006-8993(03)02679-9 (opens in a new tab)
225.
Yu XR Jia GR Gao GD Wang SH Han Y Cao W. Neuroprotection of insulin against oxidative stress-induced apoptosis in cultured retinal neurons: involvement of phosphoinositide 3-kinase/Akt signal pathway. Acta Biochim Biophys Sin. (2006 ) 38:241–8.
Not in our library10.1111/j.1745-7270.2006.00152.x (opens in a new tab)
226.
Moosavi M Maghsoudi N Zahedi-Asl S Naghdi N Yousefpour M Trounce IA. The role of PI3/Akt pathway in the protective effect of insulin against corticosterone cell death induction in hippocampal cell culture. Neuroendocrinology (2008 ) 88:293–8.
Not in our library10.1159/000150441 (opens in a new tab)
227.
Cusi K Consoli A DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. (1996 ) 81:4059–67.
Not in our library10.1210/jcem.81.11.8923861 (opens in a new tab)
228.
Hawley SA Gadalla AE Olsen GS Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes (2002 ) 51:2420–5.
Not in our library10.2337/diabetes.51.8.2420 (opens in a new tab)
229.
Adak T Samadi A Unal AZ Sabuncuoglu S. A reappraisal on metformin. Regul Toxicol Pharmacol. (2017 ) 92:324–32.
Not in our library10.1016/j.yrtph.2017.12.023 (opens in a new tab)
230.
Zakikhani M Blouin MJ Piura E Pollak MN. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat. (2010 ) 123:271–9.
Not in our library10.1007/s10549-010-0763-9 (opens in a new tab)
231.
Metformin Downregulates the Insulin/IGF-I Signaling Pathway and Inhibits Different Uterine Serous Carcinoma (USC) Cells Proliferation and Migration in p53-Dependent or -Independent Manners · 2013
No notice
232.
Memmott RM Mercado JR Maier CR Kawabata S Fox SD Dennis PA. Metformin prevents tobacco carcinogen–induced lung tumorigenesis. Cancer Prevent Res. (2010 ) 3:1066–76.
Not in our library10.1158/1940-6207.capr-10-0055 (opens in a new tab)
233.
Karnevi E Said K Andersson R Rosendahl AH. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer (2013 ) 13:235.
Not in our library10.1186/1471-2407-13-235 (opens in a new tab)
234.
Mannucci E Ognibene A Cremasco F Bardini G Mencucci A Pierazzuoli E. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care (2001 ) 24:489–94.
Not in our library10.2337/diacare.24.3.489 (opens in a new tab)
235.
Mannucci E Tesi F Bardini G Ognibene A Petracca MG Ciani S. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without Type 2 diabetes. Diabetes Nutr Metab. (2004 ) 17:336–42.
Not in our library
236.
Maida A Lamont BJ Cao X Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia (2011 ) 54:339–49.
Not in our library10.1007/s00125-010-1937-z (opens in a new tab)
237.
Athauda D Maclagan K Skene SS Bajwa-Joseph M Letchford D Chowdhury K. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet (2017 ) 390:1664–75.
Not in our library10.1016/s0140-6736(17)31585-4 (opens in a new tab)
238.
Laplante M Sabatini DM. mTOR signaling in growth control and disease. Cell (2012 ) 149:274–93.
Not in our library10.1016/j.cell.2012.03.017 (opens in a new tab)
239.
Garami A Zwartkruis FJ Nobukuni T Joaquin M Roccio M Stocker H. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell (2003 ) 11:1457–66.
Not in our library10.1016/s1097-2765(03)00220-x (opens in a new tab)
240.
Sarbassov DD Guertin DA Ali SM Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science (2005 ) 307:1098–101.
Not in our library10.1126/science.1106148 (opens in a new tab)
241.
Walsh PT Buckler JL Zhang J Gelman AE Dalton NM Taylor DK. PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J Clin Invest. (2006 ) 116:2521–31.
Not in our library10.1172/jci28057 (opens in a new tab)
242.
Garcia-Cao I Song MS Hobbs RM Laurent G Giorgi C de Boer VC. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell (2012 ) 149:49–62.
Not in our library10.1016/j.cell.2012.02.030 (opens in a new tab)
243.
Inoki K Zhu T Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell (2003 ) 115:577–90.
Not in our library10.1016/s0092-8674(03)00929-2 (opens in a new tab)
244.
Gwinn DM Shackelford DB Egan DF Mihaylova MM Mery A Vasquez DS. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell (2008 ) 30:214–26.
Not in our library10.1016/j.molcel.2008.03.003 (opens in a new tab)
245.
Brown EJ Beal PA Keith CT Chen J Shin TB Schreiber SL. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature (1995 ) 377:441–6.
Not in our library10.1038/377441a0 (opens in a new tab)
246.
Brunn GJ Hudson CC Sekulic A Williams JM Hosoi H Houghton PJ. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science (1997 ) 277:99–101.
Not in our library10.1126/science.277.5322.99 (opens in a new tab)
247.
Yip CK Murata K Walz T Sabatini DM Kang SA. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell (2010 ) 38:768–74.
Not in our library10.1016/j.molcel.2010.05.017 (opens in a new tab)
248.
Khamzina L Veilleux A Bergeron S Marette A. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology (2005 ) 146:1473–81.
Not in our library10.1210/en.2004-0921 (opens in a new tab)
249.
Tremblay F Krebs M Dombrowski L Brehm A Bernroider E Roth E. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes (2005 ) 54:2674–84.
Not in our library10.2337/diabetes.54.9.2674 (opens in a new tab)
250.
Um SH Frigerio F Watanabe M Picard F Joaquin M Sticker M. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature (2004 ) 431:200–5.
Not in our library10.1038/nature02866 (opens in a new tab)
251.
Siddiqui A Bhaumik D Chinta SJ Rane A Rajagopalan S Lieu CA. Mitochondrial quality control via the PGC1α-TFEB signaling pathway is compromised by parkin Q311X mutation but independently restored by rapamycin. J Neurosci. (2015 ) 35:12833–44.
Not in our library10.1523/jneurosci.0109-15.2015 (opens in a new tab)
252.
Zhang Y He X Wu X Lei M Wei Z Zhang X. Rapamycin upregulates glutamate transporter and IL-6 expression in astrocytes in a mouse model of Parkinson's disease. Cell Death Dis. (2017 ) 8:e2611.
Not in our library10.1038/cddis.2016.491 (opens in a new tab)
253.
Santini E Heiman M Greengard P Valjent E Fisone G. Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA–induced dyskinesia. Sci Signal. (2009 ) 2:ra36.
Not in our library10.1126/scisignal.2000308 (opens in a new tab)
254.
Dazert E Hall MN. mTOR signaling in disease. Curr Opin Cell Biol. (2011 ) 23:744–55.
Not in our library10.1016/j.ceb.2011.09.003 (opens in a new tab)
255.
Wang C Yu JT Miao D Wu ZC Tan MS Tan L. (2014 ) Targeting the mTOR signaling network for Alzheimer's disease therapy. Mol Neurobiol. 49:120–35.
Not in our library10.1007/s12035-013-8505-8 (opens in a new tab)
256.
Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease · 2010
Corrected
257.
Caccamo A De Pinto V Messina A Branca C Oddo S. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature. J Neurosc. (2014 ) 34:7988–98.
Not in our library10.1523/jneurosci.0777-14.2014 (opens in a new tab)
258.
Caccamo A Magri A Medina DX Wisely EV Lopez-Aranda MF Silva AJ. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies. Aging Cell (2013 ) 12:370–80.
Not in our library10.1111/acel.12057 (opens in a new tab)
259.
Shi WY Xiao D Wang L Dong LH Yan ZX Shen ZX. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis. (2012 ) 3:e275.
Not in our library10.1038/cddis.2012.13 (opens in a new tab)
260.
Nair V Pathi S Jutooru I Sreevalsan S Basha R Abdelrahim M. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis (2013 ) 34:2870–9.
Not in our library10.1093/carcin/bgt231 (opens in a new tab)
261.
Slomovitz BM Coleman RL. The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res. (2012 ) 18:5856–64.
Not in our library10.1158/1078-0432.ccr-12-0662 (opens in a new tab)
262.
Ben Sahra I Regazzetti C Robert G Laurent K Le Marchand-Brustel Y Auberger P. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. (2011 ) 71:4366–72.
Not in our library10.1158/0008-5472.can-10-1769 (opens in a new tab)
263.
Kalender A Selvaraj A Kim SY Gulati P Brule S Viollet B. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. (2010 ) 11:390–401.
Not in our library10.1016/j.cmet.2010.03.014 (opens in a new tab)
264.
Heneka MT Kummer MP Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. (2014 ) 14:463–77.
Not in our library10.1038/nri3705 (opens in a new tab)
265.
Weggen S Eriksen JL Das P Sagi SA Wang R Pietrzik CU. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature (2001 ) 414:212–6.
Not in our library10.1038/35102591 (opens in a new tab)
266.
Sastre M Dewachter I Landreth GE Willson TM Klockgether T van Leuven F. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci. (2003 ) 23:9796–804.
Not in our library10.1523/jneurosci.23-30-09796.2003 (opens in a new tab)
267.
Perlmutter LS Barron E Chui HC. Morphologic association between microglia and senile plaque amyloid in Alzheimer's disease. Neurosci Lett. (1990 ) 119:32–6.
Not in our library10.1016/0304-3940(90)90748-x (opens in a new tab)
268.
Wisniewski HM Wegiel J Wang KC Lach B. Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease. Acta Neuropathol. (1992 ) 84:117–27.
Not in our library10.1007/bf00311383 (opens in a new tab)
269.
Zhang Y Zhou B Deng B Zhang F Wu J Wang Y. Amyloid-beta induces hepatic insulin resistance in vivo via JAK2. Diabetes (2013 ) 62:1159–66.
Not in our library10.2337/db12-0670 (opens in a new tab)
270.
Vodovotz Y Lucia MS Flanders KC Chesler L Xie QW Smith TW. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease. J Exp Med. (1996 ) 184:1425–33.
Not in our library10.1084/jem.184.4.1425 (opens in a new tab)
271.
Heneka MT Wiesinger H Dumitrescu-Ozimek L Riederer P Feinstein DL Klockgether T. Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J Neuropathol Exp Neurol. (2001 ) 60:906–16.
Not in our library10.1093/jnen/60.9.906 (opens in a new tab)
272.
Bhaskar K Konerth M Kokiko-Cochran ON Cardona A Ransohoff RM Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron (2010 ) 68:19–31.
Not in our library10.1016/j.neuron.2010.08.023 (opens in a new tab)
273.
McGeer PL Itagaki S Boyes BE McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology (1988 ) 38:1285–91.
Not in our library10.1212/wnl.38.8.1285 (opens in a new tab)
274.
Damier P Hirsch EC Zhang P Agid Y Javoy-Agid F. Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience (1993 ) 52:1–6.
Not in our library10.1016/0306-4522(93)90175-f (opens in a new tab)
275.
Czlonkowska A Kohutnicka M Kurkowska-Jastrzebska I Czlonkowski A. Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease mice model. Neurodegeneration (1996 ) 5:137–43.
Not in our library10.1006/neur.1996.0020 (opens in a new tab)
276.
Sugama S Yang L Cho BP DeGiorgio LA Lorenzl S Albers DS. Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice. Brain Res. (2003 ) 964:288–94.
Not in our library10.1016/s0006-8993(02)04085-4 (opens in a new tab)
277.
Zhang W Wang T Pei Z Miller DS Wu X Block ML. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J. (2005 ) 19:533–42.
Not in our library10.1096/fj.04-2751com (opens in a new tab)
278.
Giasson BI Duda JE Murray IV Chen Q Souza JM Hurtig HI. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science (2000 ) 290:985–9.
Not in our library10.1126/science.290.5493.985 (opens in a new tab)
279.
Sancho D Enamorado M Garaude J. Innate immune function of mitochondrial metabolism. Front Immunol. (2017 ) 8:527.
Not in our library10.3389/fimmu.2017.00527 (opens in a new tab)
280.
Torres-Odio S Key J Hoepken H-H Canet-Pons J Valek L Roller B. Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation. J Neuroinflammation (2017 ) 14:154.
Not in our library10.1186/s12974-017-0928-0 (opens in a new tab)
281.
West AP Khoury-Hanold W Staron M Tal MC Pineda CM Lang SM. Mitochondrial DNA stress primes the antiviral innate immune response. Nature (2015 ) 520:553–7.
Not in our library10.1038/nature14156 (opens in a new tab)
282.
Isoda K Young JL Zirlik A MacFarlane LA Tsuboi N Gerdes N. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol. (2006 ) 26:611–7.
Not in our library10.1161/01.atv.0000201938.78044.75 (opens in a new tab)
283.
Gu J Ye S Wang S Sun W Hu Y. Metformin inhibits nuclear factor-κB activation and inflammatory cytokines expression induced by high glucose via adenosine monophosphate-activated protein kinase activation in rat glomerular mesangial cells in vitro. Chin Med J (Engl) (2014 ) 127:1755–60.
Not in our library10.3760/cma.j.issn.0366-6999.20132781 (opens in a new tab)
284.
Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity · 2014
No notice
285.
Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status · 2016
No notice
286.
Kaufman BA Li C Soleimanpour SA. Mitochondrial regulation of beta-cell function: maintaining the momentum for insulin release. Mol Aspects Med. (2015 ) 42:91–104.
Not in our library10.1016/j.mam.2015.01.004 (opens in a new tab)
287.
Lucking CB Durr A Bonifati V Vaughan J De Michele G Gasser T. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med. (2000 ) 342:1560–7.
Not in our library10.1056/nejm200005253422103 (opens in a new tab)
288.
Bonifati V Rizzu P van Baren MJ Schaap O Breedveld GJ Krieger E. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science (2003 ) 299:256–9.
Not in our library10.1126/science.1077209 (opens in a new tab)
289.
Valente EM Abou-Sleiman PM Caputo V Muqit MM Harvey K Gispert S. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science (2004 ) 304:1158–60.
Not in our library10.1126/science.1096284 (opens in a new tab)
290.
Winklhofer KF Haass C. Mitochondrial dysfunction in Parkinson's disease. Biochim Biophys Acta (2010 ) 1802:29–44.
Not in our library10.1016/j.bbadis.2009.08.013 (opens in a new tab)
291.
Exner N Treske B Paquet D Holmstrom K Schiesling C Gispert S. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci. (2007 ) 27:12413–8.
Not in our library10.1523/jneurosci.0719-07.2007 (opens in a new tab)
292.
Mortiboys H Aasly J Bandmann O. Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson's disease. Brain (2013 ) 136:3038–50.
Not in our library10.1093/brain/awt224 (opens in a new tab)
293.
Greene JC Whitworth AJ Kuo I Andrews LA Feany MB Pallanck LJ. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA. (2003 ) 100:4078–83.
Not in our library10.1073/pnas.0737556100 (opens in a new tab)
294.
Palacino JJ Sagi D Goldberg MS Krauss S Motz C Wacker M. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. (2004 ) 279:18614–22.
Not in our library10.1074/jbc.m401135200 (opens in a new tab)
295.
Park J Lee SB Lee S Kim Y Song S Kim S. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature (2006 ) 441:1157–61.
Not in our library10.1038/nature04788 (opens in a new tab)
296.
Parkinson Phenotype in Aged PINK1-Deficient Mice Is Accompanied by Progressive Mitochondrial Dysfunction in Absence of Neurodegeneration · 2009
No notice
297.
Clark IE Dodson MW Jiang C Cao JH Huh JR Seol JH. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature (2006 ) 441:1162–6.
Not in our library10.1038/nature04779 (opens in a new tab)
298.
Geisler S Holmstrom KM Skujat D Fiesel FC Rothfuss OC Kahle PJ. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. (2010 ) 12:119–31.
Not in our library10.1038/ncb2012 (opens in a new tab)
299.
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin · 2010
No notice
300.
Koyano F Okatsu K Kosako H Tamura Y Go E Kimura M. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature (2014 ) 510:162–6.
Not in our library10.1038/nature13392 (opens in a new tab)
301.
Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin · 2018
No notice
302.
Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand · 2018
No notice
303.
Morais VA Haddad D Craessaerts K De Bock PJ Swerts J Vilain S. PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science (2014 ) 344:203–7.
Not in our library10.1126/science.1249161 (opens in a new tab)
304.
Wang X Winter D Ashrafi G Schlehe J Wong YL Selkoe D. PINK1 and parkin target miro for phosphorylation and degradation to arrest mitochondrial motility. Cell (2011 ) 147:893–906.
Not in our library10.1016/j.cell.2011.10.018 (opens in a new tab)
305.
Plun-Favreau H Klupsch K Moisoi N Gandhi S Kjaer S Frith D. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat Cell Biol. (2007 ) 9:1243–52.
Not in our library10.1038/ncb1644 (opens in a new tab)
306.
PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1 · 2007
No notice
307.
Fitzgerald JC Zimprich A Carvajal Berrio DA Schindler KM Maurer B Schulte C. Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease. Brain (2017 ) 140:2444–59.
Not in our library10.1093/brain/awx202 (opens in a new tab)
308.
PINK1-Parkin-Mediated Mitophagy Protects Mitochondrial Integrity and Prevents Metabolic Stress-Induced Endothelial Injury · 2015
No notice
309.
Choi J Ravipati A Nimmagadda V Schubert M Castellani RJ Russell JW. Potential roles of PINK1 for increased PGC-1α-mediated mitochondrial fatty acid oxidation and their associations with Alzheimer disease and diabetes. Mitochondrion (2014 ) 18:41–8.
Not in our library10.1016/j.mito.2014.09.005 (opens in a new tab)
310.
Cang X Wang X Liu P Wu X Yan J Chen J. PINK1 alleviates palmitate induced insulin resistance in HepG2 cells by suppressing ROS mediated MAPK pathways. Biochem Biophys Res Commun. (2016 ) 478:431–8.
Not in our library10.1016/j.bbrc.2016.07.004 (opens in a new tab)
311.
Deas E Piipari K Machhada A Li A Gutierrez-del-Arroyo A Withers DJ. (2014 ). PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice. Open Biol. 4:140051.
Not in our library10.1098/rsob.140051 (opens in a new tab)
312.
Seillier M Pouyet L N'Guessan P Nollet M Capo F Guillaumond F. Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1. EMBO Mol Med. (2015 ) 7:802–18.
Not in our library10.15252/emmm.201404318 (opens in a new tab)
313.
Grassi D Howard S Zhou M Diaz-Perez N Urban NT Guerrero-Given D. Identification of a highly neurotoxic alpha-synuclein species inducing mitochondrial damage and mitophagy in Parkinson's disease. Proc Natl Acad Sci USA. (2018 ) 115:E2634–43.
Not in our library10.1073/pnas.1713849115 (opens in a new tab)
314.
The Mitochondrial Chaperone Protein TRAP1 Mitigates α-Synuclein Toxicity · 2012
No notice
315.
Strauss KM Martins LM Plun-Favreau H Marx FP Kautzmann S Berg D. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet. (2005 ) 14:2099–111.
Not in our library10.1093/hmg/ddi215 (opens in a new tab)
316.
Simon-Sanchez J Singleton AB. Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. Hum Mol Genet. (2008 ) 17:1988–93.
Not in our library10.1093/hmg/ddn096 (opens in a new tab)
317.
Fitzgerald JC Zimprich A Reddy Bobbili D Sharma M May P Kruger R Reply: No evidence for rare TRAP1 mutations influencing the risk of idiopathic Parkinson's disease. Brain (2018 ) 141:e17
Not in our library10.1093/brain/awx380 (opens in a new tab)
318.
Gaare JJ Nido GS Sztromwasser P Knappskog PM Dahl O Lund-Johansen M No evidence for rare TRAP1 mutations influencing the risk of idiopathic Parkinson's disease. Brain (2018 ) 141:e16
Not in our library10.1093/brain/awx378 (opens in a new tab)
319.
Rasola A Neckers L Picard D. Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells. Trends Cell Biol. (2014 ) 24:455–63.
Not in our library10.1016/j.tcb.2014.03.005 (opens in a new tab)
320.
Yoshida S Tsutsumi S Muhlebach G Sourbier C Lee MJ Lee S. Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis. Proc Natl Acad Sci USA. (2013 ) 110:E1604–12.
Not in our library10.1073/pnas.1220659110 (opens in a new tab)
321.
Sciacovelli M Guzzo G Morello V Frezza C Zheng L Nannini N. The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase. Cell Metab. (2013 ) 17:988–99.
Not in our library10.1016/j.cmet.2013.04.019 (opens in a new tab)
322.
Mills EL Kelly B Logan A Costa ASH Varma M Bryant CE. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell (2016 ) 167:457–470.e413.
Not in our library10.1016/j.cell.2016.08.064 (opens in a new tab)
323.
Matassa DS Amoroso MR Lu H Avolio R Arzeni D Procaccini C. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ. (2016 ) 23:1542–54.
Not in our library10.1038/cdd.2016.39 (opens in a new tab)
324.
Guzman JN Sanchez-Padilla J Chan CS Surmeier DJ. Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci. (2009 ) 29:11011–9.
Not in our library10.1523/jneurosci.2519-09.2009 (opens in a new tab)
325.
Swerdlow RH Burns JM Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis. J Alzheimer's Dis. (2010 ) 20(Suppl. 2):S265–79.
Not in our library10.3233/jad-2010-100339 (opens in a new tab)
326.
David DC Hauptmann S Scherping I Schuessel K Keil U Rizzu P. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem. (2005 ) 280:23802–14.
Not in our library10.1074/jbc.m500356200 (opens in a new tab)
327.
Rhein V Song X Wiesner A Ittner LM Baysang G Meier F. Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proc Natl Acad Sci USA. (2009 ) 106:20057–62.
Not in our library10.1073/pnas.0905529106 (opens in a new tab)
328.
Vossel KA Zhang K Brodbeck J Daub AC Sharma P Finkbeiner S. Tau reduction prevents Abeta-induced defects in axonal transport. Science (2010 ) 330:198.
Not in our library10.1126/science.1194653 (opens in a new tab)
329.
Calkins MJ Reddy PH. Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer's disease neurons. Biochim Biophys Acta (2011 ) 1812:507–13.
Not in our library10.1016/j.bbadis.2011.01.007 (opens in a new tab)
330.
Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol. (2005 ) 58:495–505.
Not in our library10.1002/ana.20624 (opens in a new tab)
331.
Bubber P Haroutunian V Fisch G Blass JP Gibson GE. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol. (2005 ) 57:695–703.
Not in our library10.1002/ana.20474 (opens in a new tab)
332.
Johri A Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther. (2012 ) 342:619–30.
Not in our library10.1124/jpet.112.192138 (opens in a new tab)
333.
Schapira AH Jenner P. Etiology and pathogenesis of Parkinson's disease. Mov Disord. (2011 ) 26:1049–55.
Not in our library10.1002/mds.23732 (opens in a new tab)
334.
Cadenas E Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. (2000 ) 29:222–30.
Not in our library10.1016/s0891-5849(00)00317-8 (opens in a new tab)
335.
Li N Oquendo E Capaldi RA Robinson JP He YD Hamadeh HK. A systematic assessment of mitochondrial function identified novel signatures for drug-induced mitochondrial disruption in cells. Toxicol Sci (2014 ) 142:261–73.
Not in our library10.1093/toxsci/kfu176 (opens in a new tab)
336.
Lopez-Otin C Blasco MA Partridge L Serrano M Kroemer G. The hallmarks of aging. Cell (2013 ) 153:1194–217.
Not in our library10.1016/j.cell.2013.05.039 (opens in a new tab)
337.
Pakendorf B Stoneking M. MITOCHONDRIAL DNA AND HUMAN EVOLUTION. Annu Rev Genomics Hum Genet. (2005 ) 6:165–83.
Not in our library10.1146/annurev.genom.6.080604.162249 (opens in a new tab)
338.
Houtkooper RH Mouchiroud L Ryu D Moullan N Katsyuba E Knott G. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature (2013 ) 497:451–7.
Not in our library10.1038/nature12188 (opens in a new tab)
339.
Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease · 2016
No notice
340.
Finkel T. Signal transduction by reactive oxygen species. J Cell Biol. (2011 ) 194:7–15.
Not in our library10.1083/jcb.201102095 (opens in a new tab)
341.
Giorgio M Trinei M Migliaccio E Pelicci PG. Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Rev Mol Cell Biol. (2007 ) 8:722–8.
Not in our library10.1038/nrm2240 (opens in a new tab)
342.
Andersen JK Oxidative stress in neurodegeneration: cause or consequence? Nat Med. (2004 ) 10(Suppl.) S18–25.
Not in our library10.1038/nrn1434 (opens in a new tab)
343.
Andrews ZB Diano S Horvath TL. Mitochondrial uncoupling proteins in the cns: in support of function and survival. Nat Rev Neurosci. (2005 ) 6:829.
Not in our library10.1038/nrn1767 (opens in a new tab)
344.
Kahle PJ Waak J Gasser T. DJ-1 and prevention of oxidative stress in Parkinson's disease and other age-related disorders. Free Radic Biol Med. (2009 ) 47:1354–61.
Not in our library10.1016/j.freeradbiomed.2009.08.003 (opens in a new tab)
345.
Xu J Zhong N Wang H Elias JE Kim CY Woldman I. The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Hum Mol Genet. (2005 ) 14:1231–41.
Not in our library10.1093/hmg/ddi134 (opens in a new tab)
346.
Kim RH Peters M Jang Y Shi W Pintilie M Fletcher GC. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell (2005 ) 7:263–73.
Not in our library10.1016/j.ccr.2005.02.010 (opens in a new tab)
347.
Wu L Xu H Cao L Li T Li R Feng Y. Salidroside protects against MPP+-induced neuronal injury through DJ-1-Nrf2 antioxidant pathway. Evid Based Complement Altern Med. (2017 ) 2017:5398542.
Not in our library10.1155/2017/5398542 (opens in a new tab)
348.
Zhou W Zhu M Wilson MA Petsko GA Fink AL. The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein. J Mol Biol. (2006 ) 356:1036–48.
Not in our library10.1016/j.jmb.2005.12.030 (opens in a new tab)
349.
Bjorkblom B Adilbayeva A Maple-Grodem J Piston D Okvist M Xu XM. Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity. J Biol Chem. (2013 ) 288:22809–20.
Not in our library10.1074/jbc.m113.482091 (opens in a new tab)
350.
van der Brug MP Blackinton J Chandran J Hao LY Lal A Mazan-Mamczarz K. RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. Proc Natl Acad Sci USA. (2008 ) 105:10244–9.
Not in our library10.1073/pnas.0708518105 (opens in a new tab)
351.
Lee JY Song J Kwon K Jang S Kim C Baek K. Human DJ-1 and its homologs are novel glyoxalases. Hum Mol Genet. (2012 ) 21:3215–25.
Not in our library10.1093/hmg/dds155 (opens in a new tab)
352.
Richarme G Mihoub M Dairou J Bui LC Leger T Lamouri A. Parkinsonism-associated protein DJ-1/Park7 is a major protein deglycase that repairs methylglyoxal- and glyoxal-glycated cysteine, arginine, and lysine residues. J Biol Chem. (2015 ) 290:1885–97.
Not in our library10.1074/jbc.m114.597815 (opens in a new tab)
353.
Richarme G Dairou J. Parkinsonism-associated protein DJ-1 is a bona fide deglycase. Biochem Biophys Res Commun. (2017 ) 483:387–91.
Not in our library10.1016/j.bbrc.2016.12.134 (opens in a new tab)
354.
Eberhard D Lammert E. The role of the antioxidant protein DJ-1 in type 2 diabetes mellitus. Adv Exp Med Biol. (2017 ) 1037:173–86.
Not in our library10.1007/978-981-10-6583-5_11 (opens in a new tab)
355.
De Jager J Kooy A Lehert P Wulffelé MG Van Der Kolk J Bets D. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010 ) BMJ 340:c2181.
Not in our library10.1136/bmj.c2181 (opens in a new tab)
356.
Warasila W Forget the Blood of Teens. This Pill Promises to Extend Life for a Nickel a Pop. Wired Magazine (2017 ).
Not in our library
357.
Lane N Power, Sex, Suicide. Mitochondria and the Meaning of Life. Oxford: Oxford University Press (2005 ).
Not in our library
358.
Barzilai N Crandall JP Kritchevsky SB Espeland MA. Metformin as a tool to target aging. Cell Metab. (2016 ) 23:1060–5.
Not in our library10.1016/j.cmet.2016.05.011 (opens in a new tab)

Cited by papers we hold 10

Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities · 2023
No notice
Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives · 2022
Corrected
Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice · 2021
Not checked
Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus · 2021
No notice
Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook · 2021
No notice
Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome · 2021
No notice
Connecting Alzheimer’s Disease With Diabetes Mellitus Through Amyloidogenic Evolvability · 2020
Not checked
Mitochondrial hyperactivity as a potential therapeutic target in Parkinson’s disease · 2020
Not checked
Impaired dopamine metabolism in Parkinson’s disease pathogenesis · 2019
No notice
Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences · 2018
No notice

Questions about this paper

We email you if it is retracted, withdrawn, corrected or flagged.

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.