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Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

Elena Tamagno, Michela Guglielmotto, Valeria Vasciaveo and 1 more

Antioxidants · 2021 · Review · CC BY

Abstract

The pathogenesis of Alzheimer’s disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain’s vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer’s disease. OS and Aβ are linked to each other because Aβ induces OS, and OS increases the Aβ deposition. Thus, the answer to the question “which comes first: the chicken or the egg?” remains extremely difficult. In any case, the evidence for the primary occurrence of oxidative stress in AD is attractive. Thus, evidence indicates that a long period of gradual oxidative damage accumulation precedes and results in the appearance of clinical and pathological AD symptoms, including Aβ deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline. Moreover, oxidative stress plays a crucial role in the pathogenesis of many risk factors for AD. Alzheimer’s disease begins many years before its symptoms, and antioxidant treatment can be an important therapeutic target for attacking the disease.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1Alzheimer’s disease (AD) is considered the leading cause of dementia and is becoming one of the most expensive and deadly diseases of our time. Thus, it is estimated that 50 million people worldwide endure dementia, and this number is set to rise to 152 million in 2050. Moreover, Alzheimer’s patients need specialized and expensive care, the annual cost of treatment worldwide is around a trillion US dollars, and it is predicted that this cost will significantly increase by 2030.

2The pathophysiology of the disease is complex and multifactorial and certainly not entirely known. There are two markers of the disease. One is β amyloid (Aβ), which accumulates abnormally in AD brain tissues and forms extracellular plaques known to induce synaptic alterations and neurodegeneration. The other is Tau protein, which forms intracellular neurofibrillary tangles that are also responsible for neurodegeneration.

3AD is traditionally divided into two forms: early and late onset forms. The early onset form is closely associated with mutations on three genes: the genes that encode for the amyloid precursor (APP) and for presenilin 1 and presenilin 2, which represent the catalytic core of γ-secretase, a key enzyme for the production of Aβ. The late onset form is caused by complex interactions between genetic and environmental factors. APOE is the gene that was first associated with the development of the late form compared to other predisposing genes that have been described. These include genes involved in neuroinflammation (such as TREM2, TYROBP, and CD33), memory (CR1, PICALM, and BIN1), and lipid metabolism (ABCA7 and CLU).

4Thus, although there are numerous factors associated with the development of the disease, Aβ represents one that is the most closely related to its pathogenesis. Aβ is composed of polypeptides of various lengths, and most of those found in the plaques are 40 and 42 amino acids long. Aβ 40 is the most abundant form and accounts for 90% of the amyloid present in the plaques; however, the longer form (Aβ 42) is predominant in the initial phases and aggregates faster than Aβ 40. Aβ is produced from the amyloid precursor protein (APP). APP is an integral membrane protein with a large, extracellular N-terminus and a shorter, cytoplasmic C-terminus. The amyloidogenic processing of APP involves two sequential cleavages operated by the β-secretases and γ-secretases. The β-secretase (BACE1) cleaves APP, generating an extracellular soluble fragment called sβAPP and an intracellular C-terminal end termed C99. C99 is further cleaved, within the membrane, by the γ-secretase. The γ-cleavage produces Aβ fragments of different lengths, and these are predominantly Aβ 40 and Aβ 42.

5In the last 30 years, many authors supported the hypothesis of the “amyloid cascade” that considers Aβ to possess a crucial role in the pathogenesis of the disease. According to this theory, the accumulation and deposition of Aβ is responsible for Tau aggregation and, therefore, for the cognitive and mnemonic decline observed in AD patients.

6However, neither the rate of dementia nor the extent of neurological damage is correlated with the Aβ aggregates. Studies on transgenic mice carrying mutations in the gene for APP demonstrated the existence of soluble Aβ (sAβ) oligomers long before the deposition of β-amyloid, further supporting the hypothesis that, in particular conditions such as over-production, soluble Aβ aggregates exist in the human brain even in the absence of plaques. The term soluble Aβ is a working definition, which combines all forms of Aβ derived from physiological brain extracts that remain in aqueous solution after high-speed centrifugation. Soluble oligomers released by cells have been shown to cause neuronal dysfunction in vivo as well as synaptic loss and cognitive impairment.

7Studies on Down Syndrome (DS) demonstrate that the presence of the APP gene in triplicate is most likely the cause of the early onset of signs of dementia in people with DS, see review. Moreover, the accumulation of Aβ is thought to play a fundamental role in triggering synaptic dysfunction in neurons and results in their eventual loss. Experimentally, soluble Aβ oligomers have been found to selectively block hippocampal long-term potentiation (LTP), widely believed to underlie learning and memory. Importantly, active and passive Aβ immunotherapies have been shown to protect against the neuropathological and cognitive deficits observed in APP transgenic models of AD and in AD patients.

8Furthermore, the existence of a relationship between the molecular model of sAβ and the phenotype of the disease was suspected, and this connection reflected the type and degree of neurotoxicity of Aβ. The species of sAβ associated with physiological aging of the brain were compared with those present in sporadic cases of Alzheimer’s disease, and it was found that the species of sAβ in the two different conditions are different. However, it must be emphasized that a recent paper has not found differences in homomeric, heteromeric and soluble Aβ between normal and Ad brains.

9It has also been observed by Tagliavini’s group that the assembly of mixtures of Aβ peptides into different Aβ seeds results in the formation of different subtypes of amyloid with distinctive physicochemical and biological properties resulting in the generation of distinct AD molecular subgroups. Selkoe’s group suggested that preventing soluble Aβ oligomer formation and targeting their N-terminal residues with antibodies could be an attractive combined therapeutic approach.

10Thus, there is a balance between Aβ synthesis and degradation through self-regulatory pathways. However, the destruction of this equilibrium results in the overproduction of Aβ in brain tissue. One of the main mechanisms that break this balance is oxidative stress (OS) and neuroinflammation. OS is caused by a derangement between the production of reactive oxygen species (ROS) and the antioxidant defences of an organism.

11OS and Aβ are linked to each other because Aβ induces OS in vivo and in vitro, and OS increases the production of Aβ.

2. Aβ vs. Oxidative stress

12There are numerous mechanisms described in the literature by which beta amyloid (Aβ) mediates oxidative damage (Figure 1).

2.1. Mitochondria

13Aβ interferes with the normal mitochondrial activity, causing dysfunction that results in oxidative stress. Thus, neurons are cells that require high energy levels to perform numerous functions, such as the generation of action potentials, nerve transmission, and axonal transport.

14The alteration of oxidative phosphorylation (OXPHOS) involves a reduction in the efficiency to transfer electrons, which in turn results in an increase in ROS production predominantly at level of complex I and complex III. These ROSs generated at the chain level unfold their damaging action mainly on mitochondrial macromolecules. The peptide Aβ not only promotes the generation of ROS at the level of the mitochondria, but inhibits, at the same time, ROS removal. In fact, it has been shown that Aβ is able to inhibit mitochondrial superoxide dismutase (MnSOD), the enzyme most involved in the detoxification of the anion superoxide and protection from peroxidative damage. Aβ is also capable of binding and inhibiting mitochondrial alcohol dehydrogenase known as ABAD (Aβ binding alcoholdehydrogenase). ABAD has a protective role, being responsible for the detoxification from aldehydes such as 4-hydroxinonenal. The interaction between the Aβ peptide and ABAD compromises the detoxification process for which the enzyme is responsible for, causing lipid peroxidation, ROS generation, and mitochondrial dysfunction.

15Furthermore, from the direct impact of Aβ on mitochondria, some authors also demonstrated that mitochondrial DNA is altered in elderly and AD patients. Various factors can influence mitochondrial activity, contributing to AD progression.. In brain tissue of AD cases, there is a downregulation of genes in mitochondrial complex I of the OXPHOS, and OS is implicated in mtDNA damage.

2.2. Transition Metals

16Another mechanism found dysregulated in AD is the homeostasis of metals such as iron (Fe), copper (Cu), and zinc (Zn). The blood–brain barrier tightly regulates the concentration of these metals, but their levels significantly increased in AD patients. Studies have shown that Aβ plaques contain traces of these metals, and Aβ can reduce Fe (III) or Cu (II) to induce hydrogen peroxide (H2O2) production, contributing to OS in AD. Moreover, some studies suggested that these metals can increase Aβ polymerization; thus, neuroblastoma cells treated with Fe3+ caused an increase in BACE1 activity that, in turn, promotes Aβ production. Moreover, zinc is also abundant in amyloid plaques, suggesting its role in AD. Zinc interacts with Aβ protein, and this interaction can be prevented by chelators. ZnAβ oligomers mediate stronger toxicity than amyloid-beta derived diffusible ligands (ADDLs) by cell viability assays. The ex vivo study showed that ZnAβ oligomers inhibited hippocampal LTP in a transgenic mouse model also through the production of ROS.

2.3. Heme

17Another important iron containing molecule that has been implicated in the pathogenesis of AD is heme. Heme is an essential molecule in various physiological and pathological mechanisms. It has been suggested that AD patients had lower hemoglobin levels and smaller cell volume with respect to normal aging controls. Complexes II, III, and IV of the electron transport chain require heme to assembly cytochromes needed to function. Perturbation in heme metabolism can cause oxidative stress and cell death. Sankar and collaborators found that heme can mitigate the Aβ 42-mediated neuroinflammation activated by astrocytes. Heme can also bind to Aβ, and this complex is known to have peroxidase activity able to oxidize serotonin and DOPA and providing an intriguing link between heme and oxidative stress in AD. Thus, heme deficiency is followed by formation of APP dimers and loss of complex IV of the electron transport chain, and this event causes OS. This finding suggested that iron accumulation observed in AD could be strictly linked to heme deficiency.

2.4. Neuroinflammation

18Another crucial mechanism through which the presence of Aβ induced oxidative stress is neuroinflammation. Neuroinflammation is considered as an immunological response characterized by the activation of glial cells and the production of inflammatory mediators. Numerous studies revealed a strong correlation between neuroinflammation and AD pathology; thus, inflammatory cytokines have been reported to increase in the progression of mild cognitive impairment to overt AD. A microarray study of Cribbs and collaborators performed on young, aged, and AD cases demonstrated an upregulation of the innate immune response in aging brains and a slight increase in related genes, suggesting that inflammation has a role in the preclinical stages of AD. In this context, microglia play a leading role in neuroinflammation. Aβ can bind different microglial receptors, resulting in the production not only of inflammatory cytokines and chemokines but also of a large amount of oxygen free radicals (•OH and O₂•), nitric oxide (•NO), and tumour necrosis factor (TNF) α. The NLR family pyrin domain containing 3 (NLRP3) inflammasome is a recently found cytoplasmic protein complex involved in neuroinflammation and innate immune response. Recent studies demonstrated that Aβ induce NLRP3 activation in microglia and astrocytes. This event results in the production of caspase 1 and induces the release of cytokines such as IL1β and IL-18, resulting in irreversible damage. On the other hand, the inhibition of NLRP3 inflammasome inhibits Aβ deposition and had a neuroprotective effect in a transgenic AD mouse model. Thus, all these findings suggest that Aβ is a crucial factor in AD associated inflammation and oxidative stress.

2.5. NF-kB Pathway

19The NF-kB family also has an important role in modulating oxidative stress. Thus, evidence from in vitro studies showed increased oxidative stress-mediated by NF-kB in response to neurons exposed to Aβ; this increased oxidative stress resulted in the accumulation of lipid peroxides and neurodegeneration. Moreover, many studies confirm that Aβ peptides stimulate NF-kB gene expression and its nuclear translocation.

3. Oxidative Stress vs. Aβ

20As mentioned in the Introduction Section, neurons, unlike other cells, use a large amount of oxygen; therefore, their mitochondria produce large amounts of ATP. This aspect is closely linked to the fact that they are production sites of reactive oxygen species and extremely sensitive to the resulting damage.

21OS increase is considered to be an early event in AD pathology, as it contributes to membrane damage, cytoskeleton alterations, and cell death.

22Thus, the identification of a large number of oxidatively modified proteins in common AD and AD animal models suggests that OS plays an important role in AD pathogenesis. Moreover, extensive oxidative damage observed in mild cognitive impairment (MCI) suggests that OS may be an early event in the progression from normal aging to AD pathology. Based on these notions, it seems likely that increased production of ROS may act as important mediators of synaptic loss and eventually promote senile plaques formation (Figure 2).

3.1. APP Processing and Secretases

23Many authors have confirmed the hypothesis that oxidative stress represents a common mechanism that mediates the accumulation and toxicity of Aβ. Therefore, oxidative stress can be considered one of the factors responsible for the accumulation of Aβ. Oxidizing agents increase the expression of APP and increase the intracellular and secreted Aβ levels. We, along with other authors, have shown that the expression and activity of BACE 1 increased in conditions of oxidative stress. Furthermore, there is a significant correlation between Bace1 activity and oxidative stress markers in brain tissues of sporadic AD in which BACE1 levels have also been shown to significantly increased compared to normal aging.

24Many authors proposed a sequence of events that observe oxidative stress, the hyper-expression of BACE1, and the induction of apoptosis connected with the deposition of Aβ. Thus, we have shown that oxidizing agents and HNE increase the expression and activity of BACE1 in neuronally differentiated cells, without modifying the levels of APP. These events are followed by both Aβ overproduction and apoptosis

25Furthermore, it has been shown that oxidative stress increases the activity of gamma secretase both in vitro and in vivo, and the increased expression of BACE1 induced by OS is regulated by gamma secretase. These results are of great importance for understanding the pathogenesis of sporadic AD. First of all, it is shown that oxidative stress, which originates during aging, can increase the activity of both secretases (β and γ secretases) and, thus, mediate the hyper production of Aβ. Oxidative stress is the only known factor capable of increasing the cut on APP operated by γ-secretase by increasing the activity of PS1, the catalytic subunit of secretase. These results demonstrate the existence of a vicious circle in which the increased activity of γ-secretase results in an increase in the expression of BACE 1.

26Other authors also demonstrated a correlation between the induction of OS and the increase in γ-secretase cleavage on APP. Given that OS can mediate both γ-secretase and BACE1 activities, OS could be considered the molecular link between β-secretase and γ-secretase.

27Another important consideration that closely links oxidative stress to the pathogenesis of AD is the fact that many of the best-known risk factors for sporadic AD observe oxidative stress playing a crucial role in their pathogenesis.

3.2. Stroke and Hypoxia

28It is known in the literature that patients who have had strokes or cerebral infarction have an increased risk of developing AD.

29The risk becomes even higher in the presence of atherosclerotic risk factors. It has been proposed that hypoxia can alter the metabolism of APP, increasing the activity of β and γ secretase. Sun et al. demonstrated, for the first time, that hypoxia significantly increases the expression and activity of BACE1. Again, the same authors show that hypoxia increases the deposition of Aβ and the formation of senile plaques, and it also mediates mnemonic deficit, suggesting a mechanism capable of linking vascular damage with AD.

30Hypoxia is also capable of increasing the activity of γ-secretase; thus, hypoxia inducible factor (HIF)-1α binds the promoter of anteriorpharynx-defectivephenotype (APH-1), a key component of the secretase γ complex, inducing its hyper regulation.

31Taken together, these data show that hypoxia increases the activity of both secretases, thus resulting in an overproduction of Aβ and the formation of plaques in both in vivo and in vitro models. It is well known that the only effective treatment for cerebral ischemic disease is the rapid restoration of the blood flow to the brain. However, reperfusion often aggravates brain injury, resulting in cerebral ischemia/reperfusion (I/R) injury. The pathophysiological process underlying cerebral I/R injury is complex. Currently, intracellular Ca2+ overloading, oxygen free radical injury, excitatory amino acid toxicity, chemokines, and white blood cell interactions are considered to be underlying pathogenic factors that contribute to cerebral I/R injury.

32It has also been shown that intracellular ROS levels change also during hypoxia; thus, ROS increases during hypoxia, and mitochondria would be their source of production under hypoxic conditions.

33It is accepted that hypoxia increases ROS via the mitochondrial transport chain and specifically by the function of complex III.

34Mitochondrial-derived ROS appears to be sufficient for stabilizing and activating HIF-1α, and it has been shown that antioxidant compounds can protect against this activation. Recently, some anticancer effects of antioxidant drugs have been precisely ascribed to the protection of events mediated by the activation of HIF-1α. Guglielmotto et al. have shown that hypoxia induces a hyper regulation of BACE1 through two different mechanisms: by inducing an early release of ROS from the mitochondria and through a later activation of HIF-1. The crucial involvement of ROS released by mitochondria was confirmed by the complete protection exerted by rotenone, which alters the complex 1 of the mitochondrial electron transport chain.

3.3. Hyperglycemia and AGEs

35Diabetes mellitus and hyperglycemia are other risks factor for AD.

36Hyperglycemia enhances the formation of advanced glycation end products (AGEs), which are senescent protein derivatives from the auto-oxidation of glucose and fructose.

37Accumulation of AGEs in various tissues is known to occur in normal aging and, at an extremely accelerated rate, in diabetes mellitus and renal failure. AGEs have been detected in vascular walls, lipoproteins, and lipid constituents where they result in macro and microangiopathy and amyloidosis.

38Increased extracellular AGEs formation was demonstrated in amyloid plaques in different cortical areas, where they may have a role in accelerating the conversion of Aβ from monomers to oligomers or higher molecular weight forms.

39In addition to post-translational protein modifications, AGEs have other pathologic effects at the cellular and molecular levels.

40An increased presence of AGEs has been observed in amyloid plaques in various cerebral cortical areas, and their role has been demonstrated in accelerating the conversion of Aβ monomers into high molecular weight oligomers. In addition to inducing post-translational changes, AGEs induce toxicity at the molecular and cellular level through other mechanisms as well. These mechanisms also include the ability to induce oxidative stress, in particular, superoxide and hydrogen peroxide. In fact, glycated proteins increase the production of free radicals compared to normal proteins. Another mechanism through which AGEs induce oxidative stress is through binding to their receptor (RAGE), a surface receptor belonging to the immunoglobulin superfamily.

41RAGE is age-dependent hyper-regulated in human tissues, and the increased interaction between AGE and RAGE induces oxidative stress, which is crucial in the pathogenesis of many aging-related diseases, such as diabetes, cardiovascular disease, and AD.

42The production of ROS induced by the interaction between AGEs and their receptor induces brain damage because it increases the vulnerability of the brain to oxidative stress. ROS increases the synthesis of Aβ, which induces the synthesis of high-mobility group box 1 (HMGB1), and S100. These molecules interact with RAGE, inducing a further production of oxygen free radicals that result in Alzheimer’s disease. Therefore, the induction of oxidative stress precedes the formation of amyloid plaques. In conclusion, we can say that the disease begins with the stress induced by the interaction between AGE and RAGE, and Aβ, HMGB1, and S100 make it progress. The reduction in the levels of AGEs and RAGE, the increase in sRAGE, and the use of antioxidants could really have benefits in the prevention and in slowing down the progression of AD. Aβ extracellular fibrillar aggregates have characteristics of AGEs and bind to RAGE in neurons and brain endothelial cells. AGE and Aβ binding to RAGEs results in further oxidative stress that contributes to neuronal death and vascular dementia in AD.

43Although the brain was once considered an insulin-independent organ, insulin signalling is now recognised as being central to neuronal health and to the function of synapses and brain circuits. Defective brain insulin signalling, as well as related signalling by insulin-like growth factor 1 (IGF-1), is associated with neurological disorders, including Alzheimer’s disease, suggesting that cognitive impairment could be related to a state of brain insulin resistance. Aβ also regulates insulin and IGF signaling in the brain by binding to the insulin receptor and disrupting its signalling capacity in in vivo monkeys injected with oligomeric Aβ. In vitro studies showed that Aβ decreases cell surface insulin receptor expression and promotes synaptic spine loss, one of the earliest structural defects observed in AD. Furthermore, insulin prevents Aβ binding to the synapses preserving synaptic integrity. Taken together, these findings suggest that AD pathological processes may be triggered or exacerbated by peripheral insulin resistance and that Aβ may itself induce brain insulin resistance and synapse loss, raising the possibility that insulin treatment may correct these pathological events. Moreover, IGF-1 protects against hyperglycaemia-induced oxidative stress, and defective insulin signalling makes neurons more vulnerable to oxidative stress.

44The fact that altered glucose metabolism precedes clinical symptoms strongly suggests that perturbed glucose homeostasis may be a cause rather than a consequence of AD. In order to sustain neuroenergetics, brain glucose levels are tightly controlled by the glucose transporter, GLUT1, at the blood–brain barrier (BBB), and its expression is directly correlated with cerebrospinal fluid (CSF) glucose levels, brain development, and function. Decreased GLUT1 expression at the BBB in AD brains has been reported. Brain glucose enters glycolytic pathways to support its urgent and complex metabolic needs. For example, neurons utilize lactate from astrocytes to support their energy demands. This phenomenon, termed the astrocyte-to-neuron lactate shuttle (ANLS), was first described by Pellerin and Magistretti in the 1990s and is supported by accumulating evidence. Notably, increased lactate is associated with tau and Aβ deposition, see review. A human in vivo PET study revealed a spatial correlation between glycolysis and Aβ deposition, suggesting a possible link between region-specific glycolysis in young brains and the subsequent development of AD pathology.

3.4. Cholesterol

45Over the past decade, hypercholesterolemia, characterized by high blood levels of cholesterol, and obesity have been considered risk factors for the development of neurodegenerative diseases. One of the mechanisms proposed to explain this correlation seems to be that high levels of cholesterol and free fatty acids result in incorrect regulation of lipid metabolism, which alters the permeability of BBB inducing neuroinflammation and cognitive deficits.

46Evidence demonstrates the hypothesis that the oxidation of cholesterol plays a crucial role in the pathogenesis of AD, and that oxysterols represent the link between AD and the alteration of lipid metabolism and hypercholesterolemia. The rationale for this hypothesis lies in the fact that oxysterols, unlike cholesterol, can cross the BBB. The key role of oxysterols in the pathogenesis of AD is suggested by studies that demonstrate their involvement in the modulation of neuroinflammation, in the accumulation of Aβ, and in the induction of cell death.

4. Concluding Remarks

47All data summarized in this review postulate that OS and Aβ are linked to each other because Aβ induces OS in vivo and in vitro, and OS increases the production of Aβ; for this reason, the answer to the question “did the chicken come before the egg?” remains, in our opinion, at least in part unsolved. Altogether, the evidence for the primary occurrence of oxidative stress in AD is very attractive and well supported. Zhu and colleagues, many years ago but still very relevant, have proposed a “Two-Hit” hypothesis whereby the early and progressive oxidative damage to neurons elicits a compensatory response such that the cell can exist in the overly oxidizing environment. This “oxidative steady state”, while initially instituted for protection, makes the cell vulnerable to additional insults, such as Aβ deposition, NFT formation, cell cycle aberration, etc.. More importantly, many of the above-mentioned hallmarks, in particular Aβ, are themselves the sources of oxidative stress. The overall effect is positive feedback.

48Thus, whether the chicken or the egg comes first, oxidative stress certainly plays a very important role in the pathogenesis of Alzheimer’s disease, and this lays the basis for clinical interventions in AD with antioxidants.

49Endogenous antioxidants can protect against the production of free radicals and can mediate the expression of molecules that enhance the antioxidant action in neurons.

50Several studies suggested an effectiveness of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) in slowing the progression of AD. In addition, various dietary antioxidants such as Vitamin E/C, curcumin, resveratrol, and Ginko biloba have emerged as promising agents in preclinical studies. However, the efficacy of antioxidants in clinical practice still leaves open questions. Thus, preclinical intervention with antioxidant molecules could be protective against AD, while their late use is useless.

51Alzheimer’s disease pathology begins many years before its symptoms; therefore, we must take advantage of this long window to modify and modulate all known risk factors for the disease. In this context, antioxidants can be an important weapon of prevention.

References 165

1.
Lane C.A., Hardy J., Schott J.M. Alzheimer’s disease. Eur. J. Neurol. 2018;25:59-70.
Not in our library10.1111/ene.13439
2.
Drug development in Alzheimer’s disease: the path to 2025 · 2016
No notice
3.
Scheltens P., De Strooper B., Kivipelto M., Holstege H., Chételat G., Teunissen C., Cummings J., van der Flier W.M. Alzheimer’s disease. Lancet. 2021;397:1577-1590.
Not in our library10.1016/s0140-6736(20)32205-4
4.
Long J.M., Holtzman D.M. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell. 2019;179:312-339.
Not in our library10.1016/j.cell.2019.09.001
5.
Stöhr J., Watts J.C., Mensinger Z.L., Oehler A., Grillo S.K., DeArmond S.J., Prusiner S.B., Giles K. Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions. Proc. Natl. Acad. Sci. USA. 2012;109:11025-11030.
Not in our library10.1073/pnas.1206555109
6.
Yu H., Wu J. Amyloid-β: A double agent in Alzheimer’s disease? Biomed. Pharm. 2021;139:111575.
Not in our library10.1016/j.biopha.2021.111575
7.
Ji C., Sigurdsson E.M. Current Status of Clinical Trials on Tau Immunotherapies. Drugs. 2021;8:1135-1152.
Not in our library10.1007/s40265-021-01546-6
8.
“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies · 2021
No notice
9.
Mendez M.F. Early-Onset Alzheimer Disease. Neurol. Clin. 2017;35:263-281.
Not in our library10.1016/j.ncl.2017.01.005
10.
Haaksma M.L., Vilela L.R., Marengoni A., Calderón-Larrañaga A., Leoutsakos J.S., Olde Rikkert M.G.M., Melis R.J.F. Comorbidity and progression of late onset Alzheimer’s disease: A systematic review. PLoS ONE. 2017;12:e0177044.
Not in our library10.1371/journal.pone.0177044
11.
Lemche E. Early Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review. Curr. Genom. 2018;19:522-602.
Not in our library10.2174/1389202919666171229145156
12.
Zhou X., Fu A.K., Ip N.Y. APOE signaling in neurodegenerative diseases: An integrative approach targeting APOE coding and noncoding variants for disease intervention. Curr. Opin. Neurobiol. 2021;69:58-67.
Not in our library10.1016/j.conb.2021.02.001
13.
Guglielmotto M., Repetto I.E., Monteleone D., Vasciaveo V., Franchino C., Rinaldi S., Tabaton M., Tamagno E. Stroke and Amyloid-β Downregulate TREM-2 and Uch-L1 Expression that Synergistically Promote the Inflammatory Response. J. Alzheimers Dis. 2019;71:907-920.
Not in our library10.3233/jad-190494
14.
Chen M.J., Ramesha S., Weinstock L.D., Gao T., Ping L., Xiao H., Dammer E.B., Duong D.D., Levey A.I., Lah J.J., et al. Extracellular signal-regulated kinase regulates microglial immune responses in Alzheimer’s disease. J. Neurosci. Res. 2021;99:1704-1721.
Not in our library10.1002/jnr.24829
15.
Bhattacherjee A., Jung J., Zia S., Ho M., Eskandari-Sedighi G., St Laurent C.D., McCord K.A., Bains A., Sidhu G., Sarkar S., et al. The CD33 short isoform is a gain-of-function variant that enhances Aβ1-42 phagocytosis in microglia. Mol. Neurodegener. 2021;16:19.
Not in our library10.1186/s13024-021-00443-6
16.
Mitsumori R., Sakaguchi K., Shigemizu D., Mori T., Akiyama S., Ozaki K., Niida S., Shimoda N. Lower DNA methylation levels in CpG island shores of CR1, CLU, and PICALM in the blood of Japanese Alzheimer’s disease patients. PLoS ONE. 2020;15:e0239196.
Not in our library10.1371/journal.pone.0239196
17.
Xu W., Tan C.C., Cao X.P., Tan L. Alzheimer’s Disease Neuroimaging Initiative. Association of Alzheimer’s disease risk variants on the PICALM gene with PICALM expression, core biomarkers, and feature neurodegeneration. Aging. 2020;12:21202-21219.
Not in our library10.18632/aging.103814
18.
Franzmeier N., Ossenkoppele R., Brendel M., Rubinski A., Smith R., Kumar A., Mattsson-Carlgren N., Strandberg O., Duerin M., Buerger K., et al. Alzheimer’s Disease Neuroimaging Initiative (ADNI)* and the Swedish BioFINDER study. The BIN1 rs744373 Alzheimer’s disease risk SNP is associated with faster Aβ-associated tau accumulation and cognitive decline. Alzheimers Dement. 2021.
Not in our library10.1002/alz.12371
19.
Dib S., Pahnke J., Gosselet F. Role of ABCA7 in Human Health and in Alzheimer’s Disease. Int. J. Mol. Sci. 2021;22:4603.
Not in our library10.3390/ijms22094603
20.
An N., Fu Y., Shi J., Guo H.N., Yang Z.W., Li Y.C., Li S., Wang Y., Yao Z.J., Hu B. Alzheimer’s Disease Neuroimaging Initiative. Synergistic Effects of APOE and CLU May Increase the Risk of Alzheimer’s Disease: Acceleration of Atrophy in the Volumes and Shapes of the Hippocampus and Amygdala. J. Alzheimers Dis. 2021;80:1311-1327.
Not in our library10.3233/jad-201162
21.
Wälti M.A., Ravotti F., Arai H., Glabe C.G., Wall J.S., Böckmann A., Güntert P., Meier B.H., Riek R. Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril. Proc. Natl. Acad. Sci. USA. 2016;113:E4976-E4984.
Not in our library10.1073/pnas.1600749113
22.
The human β-amyloid precursor protein: biomolecular and epigenetic aspects · 2015
Not checked
23.
Wilkins H.M., Swerdlow R.H. Amyloid precursor protein processing and bioenergetics. Brain Res. Bull. 2017;133:71-79.
Not in our library10.1016/j.brainresbull.2016.08.009
24.
Vassar R., Bennett B.D., Babu-Khan S., Kahn S., Mendiaz E.A., Denis P., Teplow D.B., Ross S., Amarante P., Loeloff R., et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286:735-741.
Not in our library10.1126/science.286.5440.735
25.
Huse J.T., Doms R.W. Closing in on the amyloid cascade: Recent insights into the cell biology of Alzheimer’s disease. Mol. Neurobiol. 2000;22:81-98.
Not in our library10.1385/mn:22:1-3:081
26.
Sun Z.T., Ma C., Li G.J., Zheng X.Y., Hao Y.T., Yang Y., Wang X. Application of Antibody Fragments Against Aβ With Emphasis on Combined Application with Nanoparticles in Alzheimer’s Disease. Front. Pharmacol. 2021;12:654611.
Not in our library10.3389/fphar.2021.654611
27.
Fagiani F., Lanni C., Racchi M., Govoni S. (Dys)regulation of Synaptic Activity and Neurotransmitter Release by β-Amyloid: A Look Beyond Alzheimer’s Disease Pathogenesis. Front. Mol. Neurosci. 2021;14:635880.
Not in our library10.3389/fnmol.2021.635880
28.
Wang K., Na L., Duan M. The Pathogenesis Mechanism, Structure Properties, Potential Drugs and Therapeutic Nanoparticles against the Small Oligomers of Amyloid-β. Curr. Top Med. Chem. 2021;21:151-167.
Not in our library10.2174/1568026620666200916123000
29.
Behl T., Kaur I., Fratila O., Brata R., Bungau S. Exploring the Potential of Therapeutic Agents Targeted towards Mitigating the Events Associated with Amyloid-β Cascade in Alzheimer’s Disease. Int. J. Mol. Sci. 2020;21:7443.
Not in our library10.3390/ijms21207443
30.
Decourt B., Boumelhem F., Pope E.D., Shi J., Mari Z., Sabbagh M.N. Critical Appraisal of Amyloid Lowering Agents in AD. Curr. Neurol. Neurosci. Rep. 2021;21:39.
Not in our library10.1007/s11910-021-01125-y
31.
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease · 2020
No notice
32.
Walsh D.M., Selkoe D.J. Amyloid β-protein and beyond: The path forward in Alzheimer’s disease. Curr. Opin. Neurobiol. 2020;61:116-124.
Not in our library10.1016/j.conb.2020.02.003
33.
Tabaton M., Gambetti P. Soluble amyloid-beta in the brain: The scarlet pimpernel. J. Alzheimers Dis. 2006;9:127-132.
Not in our library10.3233/jad-2006-9s315
34.
Johannesson M., Sahlin C., Söderberg L., Basun H., Fälting J., Möller C., Zachrisson O., Sunnemark D., Svensson A., Odergren T., et al. Elevated soluble amyloid beta protofibrils in Down syndrome and Alzheimer’s disease. Mol. Cell Neurosci. 2021;114:103641.
Not in our library10.1016/j.mcn.2021.103641
35.
Klyubin I., Walsh D.M., Lemere C.A., Cullen W.K., Shankar G.M., Betts V., Spooner E.T., Jiang L., Anwyl R., Selkoe D.J., et al. Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat. Med. 2005;11:556-561.
Not in our library10.1038/nm1234
36.
Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways · 2020
Not checked
37.
Koike H., Iguchi Y., Sahashi K., Katsuno M. Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment. Molecules. 2021;26:5091.
Not in our library10.3390/molecules26165091
38.
Morgan D., Diamond D.M., Gottschall P.E., Ugen K.E., Dickey C., Hardy J., Duff K., Jantzen P., DiCarlo G., Wilcock D., et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature. 2000;408:982-985.
Not in our library10.1038/35050116
39.
Piccini A., Russo C., Gliozzi A., Relini A., Vitali A., Borghi R., Giliberto L., Armirotti A., D’Arrigo C., Bachi A., et al. beta-amyloid is different in normal aging and in Alzheimer disease. J. Biol. Chem. 2005;280:34186-34192.
Not in our library10.1074/jbc.m501694200
40.
Lana E., Gellerbring A., Jung S., Nordberg A., Unger Lithner C., Darreh-Shori T. Homomeric and Heteromeric Aβ Species Exist in Human Brain and CSF Regardless of Alzheimer’s Disease Status and Risk Genotype. Front. Mol. Neurosci. 2019;12:176.
Not in our library10.3389/fnmol.2019.00176
41.
Di Fede G., Catania M., Maderna E., Ghidoni R., Benussi L., Tonoli E., Giaccone G., Moda F., Paterlini A., Campagnani I., et al. Molecular subtypes of Alzheimer’s disease. Sci. Rep. 2018;8:3269.
Not in our library10.1038/s41598-018-21641-1
42.
Decoding the synaptic dysfunction of bioactive human AD brain soluble Aβ to inspire novel therapeutic avenues for Alzheimer’s disease · 2018
Not checked
43.
Haass C., Kaether C., Thinakaran G., Sisodia S. Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect Med. 2012;2:a006270.
Not in our library10.1101/cshperspect.a006270
44.
Chang Y.T., Chang W.N., Tsai N.W., Huang C.C., Kung C.T., Su Y.J., Lin W.C., Cheng B.C., Su C.M., Chiang Y.F., et al. The roles of biomarkers of oxidative stress and antioxidant in Alzheimer’s disease: A systematic review. Biomed. Res. Int. 2014;2014:182303.
Not in our library10.1155/2014/182303
45.
Tofighi N., Asle-Rousta M., Rahnema M., Amini R. Protective effect of alpha-linoleic acid on Aβ-induced oxidative stress, neuroinflammation, and memory impairment by alteration of α7 nAChR and NMDAR gene expression in the hippocampus of rats. Neurotoxicology. 2021;85:245-253.
Not in our library10.1016/j.neuro.2021.06.002
46.
Yang X., Zhi J., Leng H., Chen Y., Gao H., Ma J., Ji J., Hu Q. The piperine derivative HJ105 inhibits Aβ1-42-induced neuroinflammation and oxidative damage via the Keap1-Nrf2-TXNIP axis. Phytomedicine. 2021;20:153571.
Not in our library10.1016/j.phymed.2021.153571
47.
Kimura A.M., Tsuji M., Yasumoto T., Mori Y., Oguchi T., Tsuji Y., Umino M., Umino A., Nishikawa T., Nakamura S., et al. Myricetin prevents high molecular weight Aβ1-42 oligomer-induced neurotoxicity through antioxidant effects in cell membranes and mitochondria. Free Radic. Biol. Med. 2021;171:232-244.
Not in our library10.1016/j.freeradbiomed.2021.05.019
48.
Meng M., Zhang L., Ai D., Wu H., Peng W. β-Asarone Ameliorates β-Amyloid-Induced Neurotoxicity in PC12 Cells by Activating P13K/Akt/Nrf2 Signaling Pathway. Front. Pharmacol. 2021;12:659955.
Not in our library10.3389/fphar.2021.659955
49.
Tamagno E., Robino G., Obbili A., Bardini P., Aragno M., Parola M., Danni O. H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38MAPK. Exp. Neurol. 2003;180:144-155.
Not in our library10.1016/s0014-4886(02)00059-6
50.
Zuo L., Hemmelgarn B.T., Chuang C.C., Best T.M. The Role of Oxidative Stress-Induced Epigenetic Alterations in Amyloid-β Production in Alzheimer’s Disease. Oxid. Med. Cell Longev. 2015;2015:604658.
Not in our library10.1155/2015/604658
51.
Bhatia V., Sharma S. Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer’s disease. J. Neurol. Sci. 2021;421:117253.
Not in our library10.1016/j.jns.2020.117253
52.
Mitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy · 2014
No notice
53.
Desler C., Lillenes M.S., Tønjum T., Rasmussen L.J. The Role of Mitochondrial Dysfunction in the Progression of Alzheimer’s Disease. Curr. Med. Chem. 2018;25:5578-5587.
Not in our library10.2174/0929867324666170616110111
54.
Anantharaman M., Tangpong J., Keller J.N., Murphy M.P., Markesbery W.R., Kiningham K.K., St Clair D.K. Beta-amyloid mediated nitration of manganese superoxide dismutase: Implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer’s disease. Am. J. Pathol. 2006;168:1608-1618.
Not in our library10.2353/ajpath.2006.051223
55.
Sen A., Nelson T.J., Alkon D.L., Hongpaisan J. Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons of Alzheimer’s Disease Hippocampus. J. Alzheimers Dis. 2018;63:1173-1189.
Not in our library10.3233/jad-171008
56.
Yao J., Du H., Yan S., Fang F., Wang C., Lue L.F., Guo L., Chen D., Stern D.M., Gunn Moore F.J., et al. Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer’s disease. J. Neurosci. 2011;31:2313-2320.
Not in our library10.1523/jneurosci.4717-10.2011
57.
Epigenetics of Alzheimer’s Disease · 2021
No notice
58.
Swerdlow R.H., Burns J.M., Khan S.M. The Alzheimer’s disease mitochondrial cascade hypothesis: Progress and perspectives. Biochim. Biophys. Acta. 2014;1842:1219-1231.
Not in our library10.1016/j.bbadis.2013.09.010
59.
Detaille D., Pasdois P., Sémont A., Dos Santos P., Diolez P. An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals. PLoS ONE. 2019;14:e0216385.
Not in our library10.1371/journal.pone.0216385
60.
Bennett J.P. Medical hypothesis: Neurodegenerative diseases arise from oxidative damage to electron tunneling proteins in mitochondria. Med. Hypotheses. 2019;127:1-4.
Not in our library10.1016/j.mehy.2019.03.034
61.
Qi Z., Liu K.J. The interaction of zinc and the blood-brain barrier under physiological and ischemic conditions. Toxicol. Appl. Pharmacol. 2019;364:114-119.
Not in our library10.1016/j.taap.2018.12.018
62.
Iron uptake and transport across physiological barriers · 2016
No notice
63.
Lovell M.A., Robertson J.D., Teesdale W.J., Campbell J.L., Markesbery W.R. Copper, iron and zinc in Alzheimer’s disease senile plaques. J. Neurol. Sci. 1998;158:47-52.
Not in our library10.1016/s0022-510x(98)00092-6
64.
Huang X., Atwood C.S., Hartshorn M.A., Multhaup G., Goldstein L.E., Scarpa R.C., Cuajungco M.P., Gray D.N., Lim J., Moir R.D., et al. The A beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. 1999;38:7609-7616.
Not in our library10.1021/bi990438f
65.
Banerjee P., Sahoo A., Anand S., Ganguly A., Righi G., Bovicelli. P., Saso L., Chakrabarti S. Multiple mechanisms of iron-induced amyloid beta-peptide accumulation in SHSY5Y cells: Protective action of negletein. Neuromolecular Med. 2014;16:787-798.
Not in our library10.1007/s12017-014-8328-4
66.
Suh S.W., Jensen K.B., Jensen M.S., Silva D.S., Kesslak P.J., Danscher G., Frederickson C.J. Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer’s diseased brains. Brain Res. 2000;852:274-278.
Not in our library10.1016/s0006-8993(99)02096-x
67.
Zhang L.H., Wang X., Zheng Z.H., Ren H., Stoltenberg M., Danscher G., Huang L., Rong M., Wang Z.Y. Altered expression and distribution of zinc transporters in APP/PS1 transgenic mouse brain. Neurobiol. Aging. 2010;31:74-87.
Not in our library10.1016/j.neurobiolaging.2008.02.018
68.
Zinc ion rapidly induces toxic, off-pathway amyloid-β oligomers distinct from amyloid-β derived diffusible ligands in Alzheimer’s disease · 2018
No notice
69.
Heme, an Essential Nutrient from Dietary Proteins, Critically Impacts Diverse Physiological and Pathological Processes · 2014
No notice
70.
Faux N.G., Rembach A., Wiley J., Ellis K.A., Ames D., Fowler C.J., Martins R.N., Pertile K.K., Rumble R.L., Trounson B., et al. An anemia of Alzheimer’s disease. Mol. Psychiatry. 2014;19:1227-1234.
Not in our library10.1038/mp.2013.178
71.
Gozzelino R. The Pathophysiology of Heme in the Brain. Curr. Alzheimer Res. 2016;13:174-184.
Not in our library10.2174/1567205012666150921103304
72.
Vanacore R., Eskew J.D., Sung L., Davis T., Smith A. Safe coordinated trafficking of heme and iron with copper maintain cell homeostasis: Modules from the hemopexin system. Biometals. 2019;2:355-367.
Not in our library10.1007/s10534-019-00194-4
73.
Sankar S.B., Donegan R.K., Shah K.J., Reddi A.R., Wood L.B. Heme and hemoglobin suppress amyloid β-mediated inflammatory activation of mouse astrocytes. J. Biol. Chem. 2018;293:11358-11373.
Not in our library10.1074/jbc.ra117.001050
74.
Atamna H. Heme binding to Amyloid-beta peptide: Mechanistic role in Alzheimer’s disease. J. Alzheimers Dis. 2006;10:255-266.
Not in our library10.3233/jad-2006-102-310
75.
Atamna H., Liu J., Ames B.N. Heme deficiency selectively interrupts assembly of mitochondrial complex IV in human fibroblasts: Revelance to aging. J. Biol. Chem. 2001;276:48410-48416.
Not in our library10.1074/jbc.m108362200
76.
Ghosh C., Seal M., Mukherjee S., Ghosh Dey S. Alzheimer’s Disease: A Heme-Aβ Perspective. Acc. Chem. Res. 2015;48:2556-2564.
Not in our library10.1021/acs.accounts.5b00102
77.
Ganguly U., Kaur U., Chakrabarti S.S., Sharma P., Agrawal B.K., Saso L., Chakrabarti S. Oxidative Stress, Neuroinflammation, and NADPH Oxidase: Implications in the Pathogenesis and Treatment of Alzheimer’s Disease. Oxid. Med. Cell Longev. 2021;2021:7086512.
Not in our library10.1155/2021/7086512
78.
Frost G.R., Jonas L.A., Li Y.M. Friend, Foe or Both? Immune Activity in Alzheimer’s Disease. Front. Aging Neurosci. 2019;11:337.
Not in our library10.3389/fnagi.2019.00337
79.
Leng F., Edison P. Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here? Nat. Rev. Neurol. 2021;17:157-172.
Not in our library10.1038/s41582-020-00435-y
80.
Villa V., Thellung S., Bajetto A., Gatta E., Robello M., Novelli F., Tasso B., Tonelli M., Florio T. Novel celecoxib analogues inhibit glial production of prostaglandin E2, nitric oxide, and oxygen radicals reverting the neuroinflammatory responses induced by misfolded prion protein fragment 90-231 or lipopolysaccharide. Pharmacol. Res. 2016;113:500-514.
Not in our library10.1016/j.phrs.2016.09.010
81.
Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates · 2021
No notice
82.
Body Fluid Cytokine Levels in Mild Cognitive Impairment and Alzheimer’s Disease: a Comparative Overview · 2014
No notice
83.
Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study · 2012
No notice
84.
Xiang Z., Haroutunian V., Ho L., Purohit D., Pasinetti G.M. Microglia activation in the brain as inflammatory biomarker of Alzheimer’s disease neuropathology and clinical dementia. Dis. Markers. 2006;22:95-102.
Not in our library10.1155/2006/276239
85.
Martínez Leo E.E., Segura Campos M.R. Systemic Oxidative Stress: A key Point in Neurodegeneration—A Review. J. Nutr. Health Aging. 2019;23:694-699.
Not in our library10.1007/s12603-019-1240-8
86.
Ashour N.H., El-Tanbouly D.M., El Sayed N.S., Khattab M.M. Roflumilast ameliorates cognitive deficits in a mouse model of amyloidogenesis and tauopathy: Involvement of nitric oxide status, Aβ extrusion transporter ABCB1, and reversal by PKA inhibitor H89. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2021;111:110366.
Not in our library10.1016/j.pnpbp.2021.110366
87.
Xu J.J., Guo S., Xue R., Xiao L., Kou J.N., Liu Y.Q., Han J.Y., Fu J.J., Wei N. Adalimumab ameliorates memory impairments and neuroinflammation in chronic cerebral hypoperfusion rats. Aging. 2021;13:14001-14014.
Not in our library10.18632/aging.203009
88.
The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease · 2016
No notice
89.
Zhang Y., Zhao Y., Zhang J., Yang G. Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease. Neurochem. Res. 2020;45:2560-2572.
Not in our library10.1007/s11064-020-03121-z
90.
The Role of Microglia and the Nlrp3 Inflammasome in Alzheimer's Disease · 2020
No notice
91.
Chiu Y.J., Lin C.H., Lee M.C., Hsieh-Li H.M., Chen C.M., Wu Y.R., Chang K.H., Lee-Chen G.J. Formulated Chinese medicine Shaoyao Gancao Tang reduces NLRP1 and NLRP3 in Alzheimer’s disease cell and mouse models for neuroprotection and cognitive improvement. Aging. 2021;9:13.
Not in our library10.18632/aging.203125
92.
Jha N.K., Jha S.K., Kar R., Nand P., Swati K., Goswami V.K. Nuclear factor-kappa β as a therapeutic target for Alzheimer’s disease. J. Neurochem. 2019;150:113-137.
Not in our library10.1111/jnc.14687
93.
Ji Y., Han J., Lee N., Yoon J.H., Youn K., Ha H.J., Yoon E., Kim D.H., Jun M. Neuroprotective Effects of Baicalein, Wogonin, and Oroxylin A on Amyloid Beta-Induced Toxicity via NF-κB/MAPK Pathway Modulation. Molecules. 2020;25:5087.
Not in our library10.3390/molecules25215087
94.
Youn K., Jun M. Geraniin Protects PC12 Cells Against Aβ25-35-Mediated Neuronal Damage: Involvement of NF-κB and MAPK Signaling Pathways. J. Med. Food. 2020;23:928-937.
Not in our library10.1089/jmf.2019.4613
95.
Ma L.Y., Liu S.F., Du J.H., Niu Y., Hou P.F., Shu Q., Ma R.R., Wu S.D., Qu Q.M., Lv Y.L. Chronic ghrelin administration suppresses IKK/NF-κB/BACE1 mediated Aβ production in primary neurons and improves cognitive function via upregulation of PP1 in STZ-diabetic rats. Neurobiol. Learn Mem. 2020;169:107155.
Not in our library10.1016/j.nlm.2019.107155
96.
Cutler R.G., Kelly J., Storie K., Pedersen W.A., Tammara A., Hatanpaa K., Troncoso J.C., Mattson M.P. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. 2004;101:2070-2075.
Not in our library10.1073/pnas.0305799101
97.
Arimon M., Takeda S., Post K., Svirsky S., Hyman B.T., Berezovska O. Oxidative stress and lipid peroxidation are upstream of amyloid pathology. Neurobiol. Dis. 2015;84:109-119.
Not in our library10.1016/j.nbd.2015.06.013
98.
Perry G., Nunomura A., Hirai K., Takeda A., Aliev G., Smith M.A. Oxidative damage in Alzheimer’s disease: The metabolic dimension. Int. J. Dev. Neurosci. 2000;18:417-421.
Not in our library10.1016/s0736-5748(00)00006-x
99.
Butterfield D.A., Castegna A. Proteomic analysis of oxidatively modified proteins in Alzheimer’s disease brain: Insights into neurodegeneration. Cell Mol. Biol. 2003;49:747-751.
Not in our library
100.
Butterfield D.A., Gnjec A., Poon H.F., Castegna A., Pierce W.M., Klein J.B., Martins R.N. Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer’s disease: An initial assessment. J. Alzheimers Dis. 2006;10:391-397.
Not in our library10.3233/jad-2006-10407
101.
Huang X., Zhao X., Li B., Cai Y., Zhang S., Yu F., Wan Q. Biomarkers for evaluating the effects of exercise interventions in patients with MCI or dementia: A systematic review and meta-analysis. Exp. Gerontol. 2021;151:111424.
Not in our library10.1016/j.exger.2021.111424
102.
Karisetty B.C., Bhatnagar A., Armour E.M., Beaver M., Zhang H., Elefant F. Amyloid-β Peptide Impact on Synaptic Function and Neuroepigenetic Gene Control Reveal New Therapeutic Strategies for Alzheimer’s Disease. Front. Mol. Neurosci. 2020;13:577622.
Not in our library10.3389/fnmol.2020.577622
103.
Saeedi M., Rashidy-Pour A. Association between chronic stress and Alzheimer’s disease: Therapeutic effects of Saffron. Biomed. Pharmacother. 2021;133:110995.
Not in our library10.1016/j.biopha.2020.110995
104.
McCarty M.F., DiNicolantonio J.J., Lerner A. A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis-And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder. Int. J. Mol. Sci. 2021;22:2140.
Not in our library10.3390/ijms22042140
105.
Patil S., Sheng L., Masserang A., Chan C. Palmitic acid-treated astrocytes induce BACE1 upregulation and accumulation of C-terminal fragment of APP in primary cortical neurons. Neurosci. Lett. 2006;406:55-59.
Not in our library10.1016/j.neulet.2006.07.015
106.
Hernández-Rodríguez M., Arciniega-Martínez I.M., García-Marín I.D., Correa-Basurto J., Rosales-Hernández M.C. Chronic Administration of Scopolamine Increased GSK3βP9, Beta Secretase, Amyloid Beta, and Oxidative Stress in the Hippocampus of Wistar Rats. Mol. Neurobiol. 2020;57:3979-3988.
Not in our library10.1007/s12035-020-02009-x
107.
Tamagno E., Bardini P., Obbili A., Vitali A., Borghi R., Zaccheo D., Pronzato M.A., Danni O., Smith M.A., Perry G., et al. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol. Dis. 2002;10:279-288.
Not in our library10.1006/nbdi.2002.0515
108.
Tong Y., Zhou W., Fung V., Christensen M.A., Qing H., Sun X., Song W. Oxidative stress potentiates BACE1 gene expression and Abeta generation. J. Neural. Transm. 2005;112:455-469.
Not in our library10.1007/s00702-004-0255-3
109.
Zhang J.S., Zhou S.F., Wang Q., Guo J.N., Liang H.M., Deng J.B., He W.Y. Gastrodin suppresses BACE1 expression under oxidative stress condition via inhibition of the PKR/eIF2α pathway in Alzheimer’s disease. Neuroscience. 2016;25:1-9.
Not in our library10.1016/j.neuroscience.2016.03.024
110.
Syeda T., Cannon J.R. Environmental exposures and the etiopathogenesis of Alzheimer’s disease: The potential role of BACE1 as a critical neurotoxic target. J. Biochem. Mol. Toxicol. 2021;35:e22694.
Not in our library10.1002/jbt.22694
111.
Borghi R., Patriarca S., Traverso N., Piccini A., Storace D., Garuti A., Cirmena G., Odetti P., Tabaton M. The increased activity of BACE1 correlates with oxidative stress in Alzheimer’s disease. Neurobiol. Aging. 2007;28:1009-1014.
Not in our library10.1016/j.neurobiolaging.2006.05.004
112.
Fukumoto H., Cheung B.S., Hyman B.T., Irizarry M.C. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch. Neurol. 2002;59:1381-1389.
Not in our library10.1001/archneur.59.9.1381
113.
Sun X., Bromley-Brits K., Song W. Regulation of β-site APP-cleaving enzyme 1 gene expression and its role in Alzheimer’s disease. J. Neurochem. 2012;120:62-70.
Not in our library10.1111/j.1471-4159.2011.07515.x
114.
Tamagno E., Guglielmotto M., Bardini P., Santoro G., Davit A., Di Simone D., Danni O., Tabaton M. Dehydroepiandrosterone reduces expression and activity of BACE in NT2 neurons exposed to oxidative stress. Neurobiol. Dis. 2003;14:291-301.
Not in our library10.1016/s0969-9961(03)00131-1
115.
Tamagno E., Parola M., Bardini P., Piccini A., Borghi R., Guglielmotto M., Santoro G., Davit A., Danni O., Smith M.A., et al. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J. Neurochem. 2005;92:628-636.
Not in our library10.1111/j.1471-4159.2004.02895.x
116.
Tamagno E., Guglielmotto M., Aragno M., Borghi R., Autelli R., Giliberto L., Muraca G., Danni O., Zhu X., Smith M.A., et al. Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J. Neurochem. 2008;104:683-695.
Not in our library10.1111/j.1471-4159.2007.05072.x
117.
Jo D.G., Arumugam T.V., Woo H.N., Park J.S., Tang S.C., Mughal M., Hyun D.H., Park J.-H., Choi Y.H., Gwon A.R., et al. Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer’s disease. Neurobiol. Aging. 2010;31:917-925.
Not in our library10.1016/j.neurobiolaging.2008.07.003
118.
Giliberto L., Borghi R., Piccini A., Mangerini R., Sorbi S., Cirmena G., Garuti A., Ghetti B., Tagliavini F., Mughal M.R., et al. Mutant presenilin 1 increases the expression and activity of BACE1. J. Biol. Chem. 2009;284:9027-9038.
Not in our library10.1074/jbc.m805685200
119.
Jin S.M., Cho H.J., Jung E.S., Shim M.Y., Mook-Jung I. DNA damage-inducing agents elicit gamma-secretase activation mediated by oxidative stress. Cell Death Differ. 2008;15:1375-1384.
Not in our library10.1038/cdd.2008.49
120.
Sheng B., Gong K., Niu Y., Liu L., Yan Y., Lu G., Zhang L., Hu M., Zhao N., Zhang X., et al. Inhibition of gamma-secretase activity reduces Abeta production, reduces oxidative stress, increases mitochondrial activity and leads to reduced vulnerability to apoptosis: Implications for the treatment of Alzheimer’s disease. Free Radic. Biol. Med. 2009;46:1362-1375.
Not in our library10.1016/j.freeradbiomed.2009.02.018
121.
Masand N., Gupta S.P., Khosa R.L. Designing of Selective γ-Secretase Inhibitory Benzenesulfonamides through Comparative In Vitro and In Silico Analysis. Curr. Drug Discov. Technol. 2018;15:65-77.
Not in our library10.2174/1570163814666170713103440
122.
Zhou J., Yu J.T., Wang H.F., Meng X.F., Tan C.C., Wang J., Wang C., Tan L. Association between stroke and Alzheimer’s disease: Systematic review and meta-analysis. J. Alzheimers Dis. 2015;43:479-489.
Not in our library10.3233/jad-140666
123.
Neurovascular dysfunction in vascular dementia, Alzheimer’s and atherosclerosis · 2018
No notice
124.
Sun X., He G., Qing H., Zhou W., Dobie F., Cai F., Staufenbiel M., Huang L.E., Song W. Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc. Natl. Acad. Sci. USA. 2006;103:18727-18732.
Not in our library10.1073/pnas.0606298103
125.
Li L., Zhang X., Yang D., Luo G., Chen S., Le W. Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP. Neurobiol. Aging. 2009;30:1091-1098.
Not in our library10.1016/j.neurobiolaging.2007.10.011
126.
Kalogeris T., Baines C.P., Krenz M., Korthuis R.J. Cell biology of ischemia/reperfusion injury. Int. Rev. Cell Mol. Biol. 2012;298:229-317.
Not in our library10.1016/b978-0-12-394309-5.00006-7
127.
Peers C., Pearson H.A., Boyle J.P. Hypoxia and Alzheimer’s disease. Essays Biochem. 2007;43:153-164.
Not in our library10.1042/bse0430153
128.
Burtscher J., Mallet R.T., Burtscher M., Millet G.P. Hypoxia and brain aging: Neurodegeneration or neuroprotection? Ageing Res. Rev. 2021;68:101343.
Not in our library10.1016/j.arr.2021.101343
129.
Guzy R.D., Mack M.M., Schumacker P.T. Mitochondrial complex III is required for hypoxia-induced ROS production and gene transcription in yeast. Antioxid. Redox Signal. 2007;9:1317-1328.
Not in our library10.1089/ars.2007.1708
130.
Zhang Z., Yan J., Chang Y., ShiDu Yan S., Shi H. Hypoxia inducible factor-1 as a target for neurodegenerative diseases. Curr. Med. Chem. 2011;18:4335-4343.
Not in our library10.2174/092986711797200426
131.
Paredes F., Williams H.C., San Martin A. Metabolic adaptation in hypoxia and cancer. Cancer Lett. 2021;502:133-142.
Not in our library10.1016/j.canlet.2020.12.020
132.
Guglielmotto M., Aragno M., Autelli R., Giliberto L., Novo E., Colombatto S., Danni O., Parola M., Smith M.A., Perry G., et al. The up-regulation of BACE1 mediated by hypoxia and ischemic injury: Role of oxidative stress and HIF1alpha. J. Neurochem. 2009;108:1045-1056.
Not in our library10.1111/j.1471-4159.2008.05858.x
133.
Diniz Pereira J., Gomes Fraga V., Morais Santos A.L., Carvalho M.D.G., Caramelli P., Braga Gomes K. Alzheimer’s disease and type 2 diabetes mellitus: A systematic review of proteomic studies. J. Neurochem. 2021;156:753-776.
Not in our library10.1111/jnc.15166
134.
Wu X.Q., Zhang D.D., Wang Y.N., Tan Y.Q., Yu X.Y., Zhao Y.Y. AGE/RAGE in diabetic kidney disease and ageing kidney. Free Radic. Biol. Med. 2021;171:260-271.
Not in our library10.1016/j.freeradbiomed.2021.05.025
135.
Iannuzzi C., Irace G., Sirangelo I. Differential effects of glycation on protein aggregation and amyloid formation. Front. Mol. Biosci. 2014;1:9.
Not in our library10.3389/fmolb.2014.00009
136.
Fawver J.N., Schall H.E., Petrofes Chapa R.D., Zhu X., Murray I.V. Amyloid-β metabolite sensing: Biochemical linking of glycation modification and misfolding. J. Alzheimers Dis. 2012;30:63-73.
Not in our library10.3233/jad-2012-112114
137.
Muscat S., Pelka J., Hegele J., Weigle B., Münch G., Pischetsrieder M. Coffee and Maillard products activate NF-kappaB in macrophages via H2O2 production. Mol. Nutr. Food Res. 2007;51:525-535.
Not in our library10.1002/mnfr.200600254
138.
Hu Z., Fang W., Liu Y., Liang H., Chen W., Wang H. Acute glucose fluctuation promotes RAGE expression via reactive oxygen species-mediated NF-κB activation in rat podocytes. Mol. Med. Rep. 2021;23:330.
Not in our library10.3892/mmr.2021.11969
139.
Prasad K. AGE-RAGE stress: A changing landscape in pathology and treatment of Alzheimer’s disease. Mol. Cell Biochem. 2019;459:95-112.
Not in our library10.1007/s11010-019-03553-4
140.
Fleming T.H., Humpert P.M., Nawroth P.P., Bierhaus A. Reactive metabolites and AGE/RAGE-mediated cellular dysfunction affect the aging process: A mini-review. Gerontology. 2011;57:435-443.
Not in our library10.1159/000322087
141.
Prasad K. AGE-RAGE stress play a role in aortic aneurysm: A comprehensive review and novel potential therapeutic target. Rev. Cardiovasc. Med. 2019;20:201-208.
Not in our library10.31083/j.rcm.2019.04.57
142.
Ramasamy R., Yan S.F., Schmidt A.M. Receptor for AGE (RAGE): Signaling mechanisms in the pathogenesis of diabetes and its complications. Ann. N. Y. Acad. Sci. 2011;1243:88-102.
Not in our library10.1111/j.1749-6632.2011.06320.x
143.
Campora M., Francesconi V., Schenone S., Tasso B., Tonelli M. Journey on Naphthoquinone and Anthraquinone Derivatives: New Insights in Alzheimer’s Disease. Pharmaceuticals. 2021;14:33.
Not in our library10.3390/ph14010033
144.
Samant N.P., Gupta G.L. Novel therapeutic strategies for Alzheimer’s disease targeting brain cholesterol homeostasis. Eur. J. Neurosci. 2021;53:673-686.
Not in our library10.1111/ejn.14949
145.
Butterfield D.A., Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci. 2019;20:148-160.
Not in our library10.1038/s41583-019-0132-6
146.
Ribe E.M., Lovestone S. Insulin signalling in Alzheimer’s disease and diabetes: From epidemiology to molecular links. J. Intern Med. 2016;280:430-442.
Not in our library10.1111/joim.12534
147.
Bomfim T.R., Forny-Germano L., Sathler L.B., Brito-Moreira J., Houzel J.C., Decker H., Silverman M.A., Kazi H., Melo H.M., McClean P.L., et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers. J. Clin. Investig. 2012;122:1339-13353.
Not in our library10.1172/jci57256
148.
Insulin in the Brain: Its Pathophysiological Implications for States Related with Central Insulin Resistance, Type 2 Diabetes and Alzheimerâ€™s Disease · 2014
No notice
149.
Loh K., Deng H., Fukushima A., Cai X., Boivin B., Galic S., Bruce C., Shields B.J., Skiba B., Ooms L.M., et al. Reactive oxygen species enhance insulin sensitivity. Cell Metab. 2009;10:260-272.
Not in our library10.1016/j.cmet.2009.08.009
150.
Rebelos E., Rinne J.O., Nuutila P., Ekblad L.L. Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review. J. Clin. Med. 2021;10:1532.
Not in our library10.3390/jcm10071532
151.
Wang D., Pascual J.M., Yang H., Engelstad K., Mao X., Cheng J., Yoo J., Noebels J.L., De Vivo D.C. A mouse model for Glut-1 haploinsufficiency. Hum. Mol. Genet. 2006;15:1169-1179.
Not in our library10.1093/hmg/ddl032
152.
Ullner P.M., Di Nardo A., Goldman J.E., Schobel S., Yang H., Engelstad K., Wang D., Sahin M., De Vivo D.C. Murine Glut-1 transporter haploinsufficiency: Postnatal deceleration of brain weight and reactive astrocytosis. Neurobiol. Dis. 2009;36:60-69.
Not in our library10.1016/j.nbd.2009.06.014
153.
Hooijmans C.R., Graven C., Dederen P.J., Tanila H., van Groen T., Kiliaan A.J. Amyloid beta deposition is related to decreased glucose transporter-1 levels and hippocampal atrophy in brains of aged APP/PS1 mice. Brain Res. 2007;1181:93-103.
Not in our library10.1016/j.brainres.2007.08.063
154.
Pang R., Wang X., Pei F., Zhang W., Shen J., Gao X., Chang C. Regular Exercise Enhances Cognitive Function and Intracephalic GLUT Expression in Alzheimer’s Disease Model Mice. J. Alzheimers Dis. 2019;72:83-96.
Not in our library10.3233/jad-190328
155.
Pellerin L., Magistretti P.J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization. Proc. Natl. Acad. Sci. USA. 1994;91:10625-10629.
Not in our library10.1073/pnas.91.22.10625
156.
Unraveling the complex metabolic nature of astrocytes · 2013
No notice
157.
Magistretti P.J., Allaman I. Lactate in the brain: From metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 2018;19:235-249.
Not in our library10.1038/nrn.2018.19
158.
Takahashi S. Neuroprotective Function of High Glycolytic Activity in Astrocytes: Common Roles in Stroke and Neurodegenerative Diseases. Int. J. Mol. Sci. 2021;22:6568.
Not in our library10.3390/ijms22126568
159.
Vlassenko A.G., Vaishnavi S.N., Couture L., Sacco D., Shannon B.J., Mach R.H., Morris J.C., Raichle M.E., Mintun M.A. Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition. Proc. Natl. Acad. Sci. USA. 2010;107:17763-17767.
Not in our library10.1073/pnas.1010461107
160.
Paul R., Borah A. Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice. Sci. Rep. 2017;7:17922.
Not in our library10.1038/s41598-017-17911-z
161.
Duong M.T., Nasrallah I.M., Wolk D.A., Chang C.C.Y., Chang T.Y. Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy. Front. Aging Neurosci. 2021;13:647990.
Not in our library10.3389/fnagi.2021.647990
162.
Testa G., Staurenghi E., Giannelli S., Gargiulo S., Guglielmotto M., Tabaton M., Tamagno E., Gamba P., Leonarduzzi G. A silver lining for 24-hydroxycholesterol in Alzheimer’s disease: The involvement of the neuroprotective enzyme sirtuin 1. Redox Biol. 2018;17:423-431.
Not in our library10.1016/j.redox.2018.05.009
163.
Gamba P., Guglielmotto M., Testa G., Monteleone D., Zerbinati C., Gargiulo S., Biasi F., Iuliano L., Giaccone G., Mauro A., et al. Up-regulation of β-amyloidogenesis in neuron-like human cells by both 24- and 27-hydroxycholesterol: Protective effect of N-acetyl-cysteine. Aging Cell. 2014;13:561-572.
Not in our library10.1111/acel.12206
164.
Zhu X., Lee H.G., Perry G., Smith M.A. Alzheimer disease, the two-hit hypothesis: An update. Biochim. Biophys. Acta. 2007;1772:494-502.
Not in our library10.1016/j.bbadis.2006.10.014
165.
Bhatt S., Puli L., Patil C.R. Role of reactive oxygen species in the progression of Alzheimer’s disease. Drug Discov. Today. 2021;26:794-803.
Not in our library10.1016/j.drudis.2020.12.004

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