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BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer’s disease

Linda Chami, Frédéric Checler

Molecular Neurodegeneration · 2012 · Review

Abstract

Alzheimer's disease (AD) is a complex age-related pathology, the etiology of which has not been firmly delineated. Among various histological stigmata, AD-affected brains display several cellular dysfunctions reflecting enhanced oxidative stress, inflammation process and calcium homeostasis disturbance. Most of these alterations are directly or indirectly linked to amyloid β-peptides (Aβ), the production, molecular nature and biophysical properties of which likely conditions the degenerative process. It is particularly noticeable that, in a reverse control process, the above-described cellular dysfunctions alter Aβ peptides levels. β-secretase βAPP-cleaving enzyme 1 (BACE1) is a key molecular contributor of this cross-talk. This enzyme is responsible for the primary cleavage generating the N-terminus of "full length" Aβ peptides and is also transcriptionally induced by several cellular stresses. This review summarizes data linking brain insults to AD-like pathology and documents the key role of BACE1 at the cross-road of a vicious cycle contributing to Aβ production.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

The amyloid beta peptides

1Alzheimer’s disease patients show progressive and irreversible memory and cognitive impairments, ultimately leading to the loss of their autonomy. This disabling disease is the first cause of dementia in the elderly population. Histopathological lesions include extracellular senile plaques mainly composed of a set of hydrophobic peptides referred to as amyloid β-peptides (A β), intracellular neurofibrillary tangles due to abnormally phosphorylated tau protein, local inflammation characterized by activated microglia and astrocytes, and neuronal loss. Several risk factors such as aging, brain insults (stroke, traumatic injury), cardiovascular diseases (hypertension), or metabolic diseases (diabetes mellitus, hypercholesterolemia, obesity) as well as genetic risk factors have been identified but the etiology of the disease is far from being fully understood.

2Aβ peptides composing the core of senile plaques are mainly produced by neuronal cells and are proteolytically derived from a transmembrane precursor protein, the βamyloid precursor protein (βAPP). βAPP undergoes subsequent cleavages by β- and γ-secretases that ultimately generate Aβ peptides. An alternative and prominent processing of βAPP by α-secretase takes place in the middle of the Aβ domain of βAPP and is regarded as a physiological non-amyloidogenic pathway.

3Even if the etiology of AD is still a matter of discussion, it is generally admitted that, if not acting as the initial trigger, Aβ peptides at least contribute to AD pathogenesis. This reasonable statement is supported by genetic data. Thus, mutations responsible for early onset and aggressive AD cases affect three genes encoding proteins involved in Aβ production, namely βAPP, and presenilin 1 and 2. All these mutations modulate the endogenous levels or nature of Aβ peptides. More recently, an additional genetic clue came from the observation that a novel mutation on βAPP that partly prevents its β-secretase-mediated cleavage and thereby reducing Aβ load, indeed protected bearers from AD in an Icelanders cohort.

4Various Aβ peptides species are found in senile deposits as well as inside cells. Their nature and length can vary drastically. Genuine “full length” Aβ peptides, that are Aβ1-40 or Aβ1-42, can undergo a variety of secondary proteolytic cleavages including N-terminal truncation and cyclisation. Moreover, monomeric soluble Aβ peptides could associate to form small soluble aggregates including oligomers and protofibrils. Soluble oligomeric species apparently display higher toxic potential for cells than Aβ monomers. Therefore, the pathology likely results from modifications of the nature and concentration of Aβ peptides, an alteration of their biophysical properties and aggregated state, and a change in their subcellular production and accumulation that are likely underlying Aβ-associated toxicity.

5In sporadic cases of AD, there is no evidence for an up-regulation of Aβ production and it is widely admitted that Aβ accumulation derives from impairment/alteration of its degradation/clearance. Amyloid peptides are mainly degraded enzymatically by neprilysin, but also and, likely to a lesser extent, by insulin degrading enzyme (IDE), endothelin-converting enzyme (ECE), angiotensin-converting enzyme (ACE), and plasmin. Neprilysin mRNA and proteins are reduced in brain areas vulnerable to amyloid deposits as is neprilysin activity in AD brains.

6βAPP and its proteolytic fragments are involved in complex networks and several feedback loops have been suggested. Furthermore Aβ would be able to induce its own production. Thus, the treatment of human NT2N neurons with Aβ peptide increased βAPP processing and production of Aβ peptides. Aβ peptide can activate its own production by binding to the promoters of βAPP and BACE1, as Aβ has been recently shown to display transcription factor properties. Furthermore, more related to the purpose of the present review, Aβ can also indirectly activate its production by generating various cellular dysfunctions, as detailed below.

The β-secretase βAPP-cleaving enzyme 1

7BACE1 (Asp2, memapsin 2), a single transmembrane aspartyl-protease, was identified in 1999 as the major β-secretase-like protein. Thus, brains and primary cortical cultures derived from BACE1 knock-out mice are devoid of β-secretase-like activity and do not produce Aβ. BACE1 is mainly expressed in neurons and in reactive astrocytes, in the Golgi apparatus and endosomes of cells, where amyloid peptides are mainly produced. β-cleavage of βAPP is the rate-limiting step in Aβ generation and therefore corresponds to an interesting therapeutic target for a strategy aimed at reducing Aβ production. BACE1 is not fully selective for βAPP and other substrates have been identified, suggesting an additional role of BACE1 in immunity or sodium channels function. BACE1 knockout mice are viable and fertile but recent data indicate that these mice could harbor axon hypomyelination, schizophrenia-like and epileptic-like behaviors.

8Environmental and cellular stresses induce the expression of BACE1. BACE1 promoter harbors functional binding sites for numerous transcription factors including specificity protein 1 (Sp1;), Yin Yang 1 (YY1;), the peroxisome proliferator-activated receptor γ (PPARγ), the nuclear factor-κB (NF-κB;), the hypoxia-inducible factor 1(HIF-1;), and signal transducer and activator of transcription 3 (STAT3;). BACE1 activity increases with age and pathology. In AD brains, BACE1 is elevated in regions that develop amyloid plaques and more particularly, in neurons surrounding amyloid plaques. The purpose of this review is to describe transcriptional regulations of BACE1. BACE1 regulation by translational modification, maturation and trafficking will not be treated as they have been nicely reviewed elsewhere.

9As stated above, BACE1 is a stress-induced protease. Oxidative stress, inflammation, calcium homeostasis disturbance, hypoxia, ischemia and trauma conditions that occur in AD activate BACE1 (see below). The activation of BACE1 due to transcriptional deregulation could contribute and possibly accelerate AD pathology by increasing Aβ production. As Aβ42 peptide can activate BACE1,, a positive regulatory loop setting a vicious cycle can be delineated and is described in details below.

Oxidative stress in AD

10Reactive oxygen species (ROS) and reactive nitrogen species are normal products of cell metabolism. Their concentration is balanced by antioxidant factors and is associated to either beneficial or deleterious effects. Low to moderate free radicals concentrations are part of the physiological cellular signaling system and defense mechanisms against infection agents. Conversely, excessive oxidant conditions trigger oxidative stress that turns out to be toxic for cells by damaging lipids, proteins or nucleic acids, ultimately leading to cell death. Oxidative damage further impairs the antioxidant defense and maintains oxidative burden in the cells.

11Lifespan accumulation of free radicals results in age-associated oxidative stress, the damages of which cause cellular and organism senescence. Oxidative stress is associated to AD as an early event. Oxidative stress contributes to AD; various mechanisms have been identified, such as the oxidative inactivation of the peptidyl-prolyl cis/trans isomerase 1 (Pin1) that affects its regulation of βAPP production and tau dephosphorylation. Interestingly, amyloid deposits and neurofibrillary tangles have been postulated to be part of antioxidant strategies developed by the organism in response to age-related increase in oxidative stress (reviewed by).

Aβ generates oxidative stress

12Aβ peptides trigger oxidative stress in vitro and in vivo (reviewed by). On the one hand, Aβ induces ROS generation, with a possible contribution of metal ions. Copper and iron are present in amyloid deposits and their reduction by Aβ produces ROS. The more powerful are the Aβ species considered as the more toxic. Thus, Aβ1-42 had greater iron and copper reduction potential than Aβ1-40 in vitro, and prefibrillar and oligomeric forms of Aβ1-42 induced higher oxidative stress than fibrillar Aβ1-42 in neuronal cells. On the other hand, Aβ peptides contribute to oxidative stress by impairing the cellular antioxidant systems. Thus continuous ventricular Aβ infusion reduced the immunoreactivity of the Mn-superoxide dismutase (Mn-SOD) and proteins of the glutathione antioxidant system in rats.

Oxidative stress activates BACE1

13BACE1 activity is positively correlated to oxidative stress markers in AD brains. Treatment of cells with various oxidants increases BACE1 transcription, expression and activity. Oxidative stress regulates the γ-secretase activity as well, and treated cells produce more Aβ peptides.

14The JNK pathway is activated in response to oxidative stress, inflammatory cytokines and excitotoxic stimuli; then activated JNK positively regulates inflammation and apoptosis. JNK is activated by Aβ in neuronal cultures and high levels of activated JNK have been reported in degenerating neurons of human AD brains or transgenic mice. JNK pathway also contributes to Aβ toxicity in vitro and production. Thus JNK gene manipulation or pharmacological blockade prevented oxidative stress-induced upregulation of BACE1 in mouse fibroblasts as well as in mice. Therefore, the c-Jun N-terminal kinases (JNK) pathway is involved in BACE1 regulation by oxidative stress.

Aβ peptides regulate BACE1 by generating oxidative stress

15As detailed before, Aβ induces oxidative stress and the latter activates BACE1. Hence Aβ indirectly regulates BACE1 by generating oxidative stress. The JNK pathway and its major transcription factor activator protein-1 (AP-1) are involved in this regulation. Guglielmotto and collaborators demonstrated that pharmacological inhibition and gene depletion or mutation of JNK or downstream proteins abolished Aβ42 control of BACE1 activation in murine fibroblasts. Therefore, by inducing oxidative stress and activation of BACE1, Aβ regulates its own production (Figure 1).

Inflammation in AD

16In response to an injurious stimulus, the organism settles inflammation until the physiological homeostasis is restored. In the central nervous system, microglia is the major actor of inflammation. Resting glial cells become motile when activated and surrounds damaged cells, clear-off cellular debris and release inflammatory agents such as cytokines, chemokines, complement factors, and free radical species. These signals activate astrocytes that undergo morphological and functional changes, and thus participate to the inflammatory process. Neurons contribute to microglial activation by production of pro-inflammatory cytokines and complement proteins.

17Neuroinflammation accompanies normal aging. Aging rodents harbor increased activated microglia and astrocytes together with an increase of pro-inflammatory cytokines or a decrease of anti-inflammatory cytokines. Local and chronic neuroinflammation is a constant feature of AD, and is characterized by activated microglia and astrocytes surrounding amyloid plaques and neurofibrillary tangles. Accordingly, elevated levels of cytokines are measured in AD brains. Inflammation can exert both neuroprotective and neurotoxic functions that are directly linked to the duration of the inflammatory process. Acute inflammation is considered to be beneficial by contributing to restore the physiological integrity of tissues. Activated glial cells are thus beneficial since they clear Aβ by phagocytosis and degradation. On the other hand, sustained inflammation observed in AD brains, probably in response to continuous accumulation of Aβ peptides and cellular debris, can be toxic to neurons since inflammatory mediators such as ROS, cytokines and chemokines could directly take part to neurite retraction, neuronal dysfunction and neuronal death. The metabolites released by activated microglia add to the dual effect of inflammation, as they can be neurotoxic, antioxidant, pro- or anti-inflammatory. The role of inflammation in AD is therefore the resultant of various cellular and molecular events.

Aβ peptides are pro-inflammatory

18Aβ treatment induces an activation of microglial and astrocytic cells, leading to the release of inflammatory factors. Aβ activate glial cells by direct binding to microglial cell surface receptors, such as the receptor for advanced glycation end products (RAGE,), by direct activation of the complement system, or by generating oxidative stress.

19The transcription factor NF-κB is activated in response to various stresses. NF-κB is induced by inflammation- and oxidative stress-linked conditions such as release of cytokines and ROS, as well as ischemia or traumatic brain injury in rats. NF-κB has a dual role in inflammation, since it is associated to pro-inflammatory or anti-inflammatory genes induction during the onset or the management of inflammation, respectively.

20Aβ peptides activate NF-κB in neurons and astrocytes. The lowest Aβ concentrations were the more efficient to activate NF-κB. NF-κB activation has been reported in human cortex areas affected by the pathology, particularly in cells surrounding senile plaques. The role of NF-κB activation remains unclear. Several works suggested a protective cellular response to Aβ-induced cell death. However other studies indicated that NF-κB could contribute to Aβ-associated toxicity, as inhibition of NF-κB reduced Aβ-induced neuronal death.

Inflammation activates BACE1

21The well-known inflammation inducer lipopolysaccharide (LPS) increases βAPP expression and processing in Swedish-βAPP transgenic mice. LPS and inflammation activate the transcription factor NF-κB, for which BACE1 promoter harbors a highly conserved binding site that is functional. NF-κB physiologically represses BACE1 transcription in vitro, therefore limiting Aβ production.

22However inflammatory conditions could favor Aβ production by switching the NF-κB inhibition of BACE1 transcription towards an activation process as suggested by many studies. Thus NF-κB activates BACE1 promoter, expression and enzymatic activity in activated astrocytes and Aβ-exposed or Aβ-overproducing cells, leading to increased Aβ production. In vivo, the modulation of NF-κB activity by non-steroidal anti-inflammatory drugs, natural compounds or by targeting upstream receptors of the NF-κB activation pathway, all affect Aβ production. In transgenic mice NF-κB activates βAPP levels, BACE1 promoter activity, expression and enzymatic activity as well as γ-secretase activity and Aβ production.

23NF-κB-dependent regulation of BACE1 is therefore ambivalent, since NF-κB would physiologically repress BACE1 transcription, but would convert into an activator of BACE1 in cells exposed to an Aβ overload. This could be explained by the activation of different NF-κB heterodimers yielded in a stimulus-dependent manner even if this remains to be definitely established.

24Other mediators of inflammation contribute to the regulation of BACE1. PPARγ are nuclear receptors that inhibit pro-inflammatory gene expression such as NF-κB-regulated genes, and are targeted by some nonsteroidal anti-inflammatory drugs (NSAID,). PPARγ inhibits BACE1 transcription through a functional PPAR response element on BACE1 promoter and interferes with the cytokines-induced Aβ production, as demonstrated in cells and confirmed in transgenic mice and human brains. PPARγ agonists have additional beneficial effects on Aβ peptides production by increasing βAPP or BACE1 degradation.

25Prolonged inflammation could favor Aβ production by activating astrocytes, as demonstrated by various in vitro and in vivo studies. Thus, chronic stress, pro-inflammatory cytokines or Aβ42 itself increase BACE1 levels and activity as well as βAPP levels in astrocytes. The transcription factors NF-κB, YY1 and STAT1 could account for the stress-induced increase of BACE1 transcription in astrocytes that are observed in the vicinity of amyloid plaques in both aged Tg2576 mice and AD-affected brains. However a recent study challenges these results by showing a reduced Aβ secretion in response to cytokine stimulation of cultured rat astrocytes, in which the β-secretase activity would be accounted for by the BACE1 homolog, BACE2.

Aβ peptides regulate their own production by triggering NF-κB-mediated BACE1 activation

26At supraphysiological levels, Aβ induces an upregulation of BACE1 transcriptional activity, protein expression, enzymatic activity, and consequently intracellular accumulation and secretion of Aβ, by activating NF-κB. BACE1 transcription is therefore activated by Aβ and by inflammation. In turn, BACE1 can promote inflammation by the production of two pro-inflammatory agents that are Aβ and the prostaglandin E2, produced by BACE1 cleavage of the membrane-bound prostaglandin E2 synthase-2. Therefore by inducing inflammation and NF-κB activation, Aβ could act on its own production (Figure 2).

Calcium signaling perturbation in AD

27Calcium is a major signaling molecule involved in a variety of neuronal functions, such as neurotransmission, synaptic plasticity, excitotoxicity or apoptosis. Aging affects calcium sensitivity and homeostasis, thereby triggering neuronal vulnerability and cell death. Oxidative stress is tightly associated to these calcium homeostasis alterations.

28The calcium signaling pathway is altered in AD. Intracellular levels of calcium are increased by a disturbed entry of external calcium, an exacerbated release from the internal storage organelles endoplasmic reticulum and mitochondria, and/or an hypersensitivity of the system. The disturbed calcium signaling alters long-term potentiation and long-term depression, thus affecting learning and memory. Finally, an overload of calcium can induce the mitochondria to trigger apoptosis and neurodegeneration. The polymorphism of a calcium channel was formerly associated to an increased risk of AD. The calcium homeostasis modulator 1 (CALHM1) channel controls intracellular calcium levels and calcium-dependent α-secretase-mediated processing of βAPP. A polymorphism in its gene impairs its physiological functions and favors Aβ overload. Currently, the CALHM1 polymorphism is rather considered as a genetic modifier of age at onset in AD.

Aβ affects cellular calcium homeostasis

29Calcium homeostasis disturbance is part of Aβ neurotoxicity (for reviews see). Amyloid peptides increase the level of cytoplasmic calcium through several mechanisms, as suggested by the in vitro experiments described below. Aβ can trigger an extracellular calcium influx by stimulating membrane ion channels or receptors, such as ionotropic glutamate receptors. Aβ could impair the intracellular distribution of calcium by perforating and permeabilizing the membrane to calcium via oxidative stress. Noteworthy, some presenilin mutations responsible for familial AD and yielding enhanced Aβ levels, impair calcium homeostasis by deregulating internal calcium channels ryanodine receptor, inositol 1,4,5-triphosphate (IP3) channel or sarco endoplasmic reticulum calcium ATPase (SERCA;). This agreed well with our recent work showing that the overexpression of both wild-type and Swedish-mutated βAPP increased Ryanodine receptors (RyR) expression and enhanced RyR-mediated ER Ca2+ release in neuroblastoma cells as well as in transgenic mice. Altering presenilin functions has an impact on calcium homeostasis by an additional mechanism. Concomitant to the generation of Aβ, the γ-secretase complex releases the βAPP intracellular domain (AICD) which acts as a transcription factor involved in the transactivation of genes related to AD. Similarly, AICD is involved in calcium signaling or homeostasis in different cell culture models.

Calcium disturbance activates BACE1

30Calcium dysregulation promotes tau phosphorylation and Aβ accumulation in neuronal cells. Calpain is an intracellular cystein protease regulated by calcium and abnormally activated in AD brains. In transgenic mice brains, calpain over-activation induces amyloid deposits, tau phosphorylation, activation of astrocytes, synapse loss and cognitive impairment. Furthermore, βAPP processing is affected as βAPP C-terminal fragments are decreased following calpain inhibition in these mice.

31BACE1 upregulation could be mediated by cyclin-dependent kinase 5 (cdk5), which is regulated by calpain. Cdk5 activates BACE1 promoter by binding of its target STAT3, therefore increasing BACE1 activity, Aβ1-40 and Aβ1-42 production in transgenic mice. Another calcium-dependent transcription factor regulates BACE1 transcription. The calcium-activated nuclear factor of activated T-cells 1 (NFAT1), which is abnormally activated in transgenic mice brain, translocates to the nucleus, binds to BACE1 promoter, activates its transcription and increases Aβ generation, as demonstrated in vitro.

32Many evidences thus imply a calcium-dependent activation of BACE1. However, two in vitro studies suggest that the regulation of Aβ production by calcium would be more complex. Hayley and collaborators who demonstrated a physical interaction between calcium and BACE1 reported on an activation of BACE1 activity at low calcium concentration, and conversely, a progressive reduction of BACE1 activity when increasing calcium concentration. Similar results were obtained on Aβ production using thapsigargin, a pharmacological raiser of cytoplasmic calcium levels.

Aβ peptides regulate BACE1 via calcium-dependent pathways

33As detailed above, impaired calcium homeostasis activates BACE1 via activation of NFAT1 and the calpain/cdk5/STAT3 pathway. By altering calcium signaling, Aβ regulates BACE1 through both pathways. Aβ treatment of cultured neurons activated calpain, cdk5, NFAT1 and increased BACE1 expression that was reduced by calpain inhibition or calcineurin-mediated NFAT1 inhibition. Therefore calcium is another intermediate by which Aβ upregulates BACE1, and thus its own production (Figure 3).

AGEs in AD

34AGEs are normal products of cellular metabolism. They result from irreversible post-translational modifications of proteins on which monosaccharides are grafted by non-enzymatic mechanisms. By generating protease-resistant peptides and proteins, this reaction leads to protein deposition and amyloidosis. AGEs accumulate in aged tissue and contribute to the age-related deterioration of cellular functions. AGE production can be enhanced in pathological contexts such as diabetes mellitus-associated hyperglycemia, inflammation, and hypoxia. AGEs pathogenicity is linked to the concomitant oxidative stress generated during their formation, to their interaction with its receptor RAGE, or by the accumulation of non-degradable proteins. Furthermore, AGEs binding to RAGE intensifies inflammation by activation of NF-κB and by release of pro-inflammatory cytokines. In turn, NF-κB transactivates RAGE promoter. Finally, AGEs compete with other physiological ligands interacting with RAGE, such as growth or differentiation factors.

35Cerebral levels of AGEs are increased in human AD brains, especially in neurofibrillary tangles and amyloid deposits. Tau and Aβ peptides are indeed substrates for glycation, which contributes to their pathogenicity. Thus in vitro studies showed that tau glycation impairs its ability to bind to tubulin, and AGEs favor Aβ peptides aggregation.

Aβ modulates the AGE/RAGE signaling cascade

36Aβ peptides that can be considered as AGEs, bind to RAGE and upregulate this receptor through the cytokine macrophage colony-stimulating factor (M-CSF). This amplifies RAGE sensitivity for Aβ stimulation and probably subsequent pro-inflammatory conditions settled by the microglia. Arancio and collaborators highlighted the contribution of RAGE to AD phenotype. Transgenic mice overexpressing mutant βAPP and RAGE exhibited earlier cognitive abnormalities and altered synaptic function, along with an increase in NF-κB activation and amyloid deposits-associated reactive microglia and astrocytes.

AGEs and RAGE activate BACE1

37AGEs can influence Aβ generation. AGEs induce βAPP expression by generating oxidative stress in SH-SY5Y cells and in transgenic mice model of AD, RAGE injection increases Aβ accumulation and senile plaques. As mentioned in this review, pro-oxidant conditions regulate BACE1. Similarly, BACE1 expression and activity are increased by the activation of RAGE in transgenic mice and SH-SY5Y cells. NFAT1 could be involved in this regulation, since AGEs- or Aβ-mediated stimulation of RAGE increased cytosolic calcium concentration, NFAT1 activation and binding to BACE1 promoter in SH-SY5Y cells. The NF-κB pathway seems also involved in RAGE-dependent regulation of BACE1. Thus pentosidine and glyceraldehydes-derived pyridinium, two AGEs that are increased in AD patients brains, upregulate BACE1 expression by binding with RAGE and subsequent activation of NF-κB in vitro and in vivo. Therefore, RAGE activation by AGEs or Aβ activate BACE1 transcription and thereby, increases Aβ production (Figure 4).

Traumatic brain injury

38Traumatic brain injury is a risk factor for AD. Post mortem analysis of patients who had traumatic brain injury revealed deposition of Aβ peptides in brain and abnormal distribution in the cerebrospinal fluid. This was confirmed in transgenic mice model of AD, where repetitive traumatic brain injury triggered Aβ accumulation. Traumatic brain injury is followed by an increase of BACE1 mRNA, protein and activity, as well as an accumulation of βAPP and presenilin 1.

39BACE1 activation could be due to oxidative stress and NF-κB activation following traumatic brain injury, as we previously described that both can upregulate BACE1 (Figure 5). In addition, BACE1 upregulation may result from an impaired degradation. The GGA (Golgi-localizing, γ-adaptin ear homology domain, ARF-binding) proteins regulate BACE1 trafficking between endosomes and Golgi apparatus. Following head injury, activated caspases cleave GGA1 and GGA3, thereby stabilizing BACE1.

40BACE1 deletion attenuates brain damages due to traumatic injury. Thus learning impairment and tissue damage are attenuated in BACE1 null mice. BACE1 would contribute to the continuing neuronal damage after the initial injury, where apoptotic and inflammatory pathways are activated.

Hypoxia

41Vascular risk factors, like heart disease or stroke leading to hypoperfusion are risk factors for AD. Hypoperfusion, that is a transient or permanent reduction in cerebral blood flow leading to subsequent hypoxia, causes a decrease in the important source of energy ATP, a perturbation of ionic gradients, an increase in cytoplasmic calcium concentration, an excitotoxic excess of extracellular glutamate, oxidative stress, and activation of pro-inflammatory pathways, ultimately leading to cell death.

42In response to hypoxia, BACE1 levels, maturation and activity, as well as Aβ deposition and memory deficits are increased in Swedish mutant APP mice. In this pathological condition, BACE1 transcription is activated by hypoxia-inducible factor (HIF-1), a major transcription factor induced by oxygen reduction. Guglielmotto and collaborators proposed a biphasic activation of BACE1 by hypoxia. The early phase would be characterized by the release of ROS from mitochondria and by the activation of the JNK pathway, whereas during the late phase, the HIF1α transcription factor would take over BACE1 activation. Besides oxidative stress, other hypoxia-linked mechanisms could contribute to BACE1 activation, such as the activation of calpain and cdk5, or the upregulation of RAGE or NF-κB by an HIF-1α-dependent transcriptional activation. The three mechanisms explaining hypoxia-induced BACE1 upregulation are summarized in Figure 6.

43Finally, two additional post-transcriptional mechanisms contribute to elevate BACE1 levels: the phosphorylation of eIF2α subsequent to energy deprivation that translationally activates BACE1; reduction of GGA3 levels following ischemia, leading to BACE1 stabilization and increased β-secretase activity.

Aβ-linked apoptosis in AD

44Aβ toxicity mediated by oxidative stress, inflammation, disturbed calcium homeostasis and cellular disorder described above, leads to apoptosis. Aβ can activate the extrinsic or the intrinsic apoptotic pathways according to its aggregation state (reviewed in). Aβ can directly induce apoptosis by activating the transcription of the tumor suppressor p53, the expression of which is increased in AD brains. Furthermore, by activating p53, Aβ and AICD can regulate their own production, since p53 has been shown to regulate some of the γ-secretase complex proteins that are presenilin 1, presenilin 2 and presenilin enhancer 2 (Pen-2).

Conclusion

45Changes observed in AD brains are not necessarily causes of the disease, and could be consequences of the pathological process. Most of cellular responses and adaptative processes described in this review as well as Aβ peptides can exert both protective and toxic functions according to the cellular context. For Aβ peptides, those include modulating ion channel function, neuronal viability, protection from glutamate and N-methyl-D-aspartic acid excitoxicities, and reduction of oxidative damage. Aβ excess is considered to have a causative role in AD pathogenesis, but could be a protective mechanism in response to various stresses.

46Nevertheless, AD brain cells undergo various stresses mainly caused by oxidative stress, inflammation and calcium homeostasis impairment. Chronic exposition of cells to these age-related perturbations or brain insults maintains supraphysiological BACE1 levels, leading to an increased production of amyloid peptides, particularly significant since their degradation is reduced in AD. Since these peptides in turn contribute to oxidative, inflammatory and disturbed calcium conditions, this overall contributes to feed a morbid vicious cycle described in the Figure 7. According to this scheme, BACE1 activation and accompanying increase in Aβ production play a key role in the amplification of cellular dysfunctions. It should be noted that an interesting recent paper indicates that BACE1 upregulation may contribute to AD pathogenesis by disturbing synaptic functions, independently of its catalytic role in Aβ production. Thus, Chen and collaborators showed that BACE1 negatively controls the cAMP/PKA/CREB pathway by interacting adenylate cyclase. This regulation was not affected in cells devoid of Aβ. The CREB pathway is important for memory functions, and upregulation of BACE1 in mice did affect their learning and memory abilities, in the absence of βAPP fragments.

47Since BACE1 contributes to AD pathogenesis and is essential to the cycle described in Figure 7, limiting its activity is an interesting therapeutic strategy. Inhibitors of BACE1 have been developed and improved recently. Some non-peptidic orally available compounds with good pharmacological properties reduced brain Aβ levels in AD transgenic mice and already are under phase I clinical studies. One of them successfully passed phase I trial and reduced plasma Aβ levels in AD patients (for review, see). However BACE1 inhibition should not be complete to prevent potential side effects (hypomyelination, schizophrenia- and epileptic-like behaviors, hippocampal neurodegeneration) linked to BACE1-associated proteolysis of other substrates. Different therapeutic strategies aimed at reducing inflammation or oxidative damage in AD did not prove to be successfull so far. It is likely that AD treatment may need to target simultaneously distinct components/pathways to be efficient, and should be used in the early phase of development of the pathology in order to prevent irreversible damages in AD brains.

Abbreviations

48Aβ: amyloid peptide; ACE: angiotensin-converting enzyme; AD: Alzheimer’s disease; AGE: advanced glycation end products; AICD: βAPP intractellular domain; AP-1: activator protein-1; BACE1: β-secretase βAPP cleaving enzyme 1; βAPP: β-amyloid precursor protein; CALHM1: calcium homeostasis modulator 1; cdk5: cyclin-dependent kinase 5; ECE: endothelin-convertin enzyme; GGA: golgi-localizing γ-adaptin ear homology domain, ARF-binding; HIF-1: hypoxia-inducible factor 1; IDE: insulin degrading enzyme; IP3: inositol 1,4,5-triphosphate; JNK: c-Jun N-terminal kinases; LPS: lipopolysaccharide; M-CSF: macrophage colony-stimulating factor; NFAT1: nuclear factor of activated T-cells 1; NF-κB: nuclear factor-κB; NSAID: nonsteroidal anti-inflammatory drugs; Pen-2: presenilin enhancer 2; Pin-1: peptidyl-prolyl cis/trans isomerase 1; PPARγ: peroxisome proliferator-activated receptor γ; RAGE: receptor for advanced glycation end products; ROS: reactive oxygen species; SERCA: sarco endoplasmic reticulum calcium ATPase; Sp1: specificity protein 1; STAT: signal transducer and activator of transcription; YY1: Yin Yang 1.

Competing interests

49The authors declare no competing interests.

Authors’ contributions

50Manuscript drafted and edited by LC and FC. All authors read and approved the final manuscript.

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Maloney B Lahiri DK The Alzheimer's amyloid beta-peptide (Abeta) binds a specific DNA Abeta-interacting domain (AbetaID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: characterizing a new regulatory motifGene2011 488112
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19.
Bailey JA Maloney B Ge YW Lahiri DK Functional activity of the novel Alzheimer's amyloid beta-peptide interacting domain (AbetaID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesisGene2011 4881322
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20.
Vassar R Bennett BD Babu-Khan S Kahn S Mendiaz EA Denis P Teplow DB Ross S Amarante P Loeloff R Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACEScience1999 286735741
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21.
Sinha S Anderson JP Barbour R Basi GS Caccavello R Davis D Doan M Dovey HF Frigon N Hong J Purification and cloning of amyloid precursor protein beta-secretase from human brainNature1999 402537540
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22.
Yan R Bienkowski MJ Shuck ME Miao H Tory MC Pauley AM Brashier JR Stratman NC Mathews WR Buhl AE Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activityNature1999 402533537
Not in our library10.1038/990107
23.
Hussain I Powell D Howlett DR Tew DG Meek TD Chapman C Gloger IS Murphy KE Southan CD Ryan DM Identification of a novel aspartic protease (Asp 2) as beta-secretaseMol Cell Neurosci1999 14419427
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24.
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25.
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26.
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27.
Cai H Wang Y McCarthy D Wen H Borchelt DR Price DL Wong PC BACE1 is the major beta-secretase for generation of Abeta peptides by neuronsNat Neurosci2001 4233234
Not in our library10.1038/85064
28.
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Not in our library10.1385/jmn:17:2:157
29.
The Alzheimer's disease Beta-secretase enzyme, BACE1 · 2007
No notice
30.
Hu X Hicks CW He W Wong P Macklin WB Trapp BD Yan R Bace1 modulates myelination in the central and peripheral nervous systemNat Neurosci2006 915201525
Not in our library10.1038/nn1797
31.
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Not in our library10.1126/science.1132341
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Savonenko AV Melnikova T Laird FM Stewart KA Price DL Wong PC Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null miceProc Natl Acad Sci USA2008 10555855590
Not in our library10.1073/pnas.0710373105
33.
Hu X Zhou X He W Yang J Xiong W Wong P Wilson CG Yan R BACE1 deficiency causes altered neuronal activity and neurodegenerationJ Neurosci2010 3088198829
Not in our library10.1523/jneurosci.1334-10.2010
34.
Sex- and brain region-specific acceleration of β-amyloidogenesis following behavioral stress in a mouse model of Alzheimer's disease · 2010
No notice
35.
Wang Y Li M Tang J Song M Xu X Xiong J Li J Bai Y Glucocorticoids facilitate astrocytic amyloid-beta peptide deposition by increasing the expression of APP and BACE1 and decreasing the expression of amyloid-beta-degrading proteasesEndocrinology2011 15227042715
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36.
Vassar R Kovacs DM Yan R Wong PC The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potentialJ Neurosci2009 291278712794
Not in our library10.1523/jneurosci.3657-09.2009
37.
Christensen MA Zhou W Qing H Lehman A Philipsen S Song W Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1Mol Cell Biol2004 24865874
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38.
Nowak K Lange-Dohna C Zeitschel U Gunther A Luscher B Robitzki A Perez-Polo R Rossner S The transcription factor Yin Yang 1 is an activator of BACE1 expressionJ Neurochem2006 9616961707
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39.
Sastre M Dewachter I Rossner S Bogdanovic N Rosen E Borghgraef P Evert BO Dumitrescu-Ozimek L Thal DR Landreth G Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgammaProc Natl Acad Sci USA2006 103443448
Not in our library10.1073/pnas.0503839103
40.
Bourne KZ Ferrari DC Lange-Dohna C Rossner S Wood TG Perez-Polo JR Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptidesJ Neurosci Res2007 8511941204
Not in our library10.1002/jnr.21252
41.
Chen CH Zhou W Liu S Deng Y Cai F Tone M Tone Y Tong Y Song W Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's diseaseInt J Neuropsychopharmacol2011 114
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Wen Y Yu WH Maloney B Bailey J Ma J Marie I Maurin T Wang L Figueroa H Herman M Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processingNeuron2008 57680690
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44.
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45.
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47.
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48.
Stockley JH O'Neill C Understanding BACE1: essential protease for amyloid-beta production in Alzheimer's diseaseCell Mol Life Sci2008 6532653289
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51.
Tamagno E Guglielmotto M Aragno M Borghi R Autelli R Giliberto L Muraca G Danni O Zhu X Smith MA Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor proteinJ Neurochem2008 104683695
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52.
Buggia-Prevot V Sevalle J Rossner S Checler F NFkappaB-dependent control of BACE1 promoter transactivation by Abeta42J Biol Chem2008 2831003710047
Not in our library10.1074/jbc.m706579200
53.
Sadleir KR Vassar R Cdk5 protein inhibition and Abeta42 increase BACE1 protein level in primary neurons by a post-transcriptional mechanism: implications of CDK5 as a therapeutic target for Alzheimer diseaseJ Biol Chem2012 28772247235
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54.
Valko M Leibfritz D Moncol J Cronin MT Mazur M Telser J Free radicals and antioxidants in normal physiological functions and human diseaseInt J Biochem Cell Biol2007 394484
Not in our library10.1016/j.biocel.2006.07.001
55.
Harman D Free radicals in agingMol Cell Biochem1988 84155161
Not in our library10.1007/bf00421050
56.
Smith MA Perry G Richey PL Sayre LM Anderson VE Beal MF Kowall N Oxidative damage in Alzheimer'sNature1996 382120121
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57.
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58.
Oxidative stress mediates the pathogenic effect of different Alzheimer's disease risk factors · 2010
Not checked
59.
Sultana R Butterfield DA Role of Oxidative Stress in the Progression of Alzheimer's DiseaseJ Alzheimers Dis2009
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60.
Butterfield DA Abdul HM Opii W Newman SF Joshi G Ansari MA Sultana R Pin1 in Alzheimer's diseaseJ Neurochem2006 9816971706
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61.
Castellani RJ Lee HG Perry G Smith MA Antioxidant protection and neurodegenerative disease: the role of amyloid-beta and tauAm J Alzheimers Dis Other Demen2006 21126130
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Not in our library10.1021/bi990438f
63.
Huang X Cuajungco MP Atwood CS Hartshorn MA Tyndall JD Hanson GR Stokes KC Leopold M Multhaup G Goldstein LE Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reductionJ Biol Chem1999 2743711137116
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Kim HC Yamada K Nitta A Olariu A Tran MH Mizuno M Nakajima A Nagai T Kamei H Jhoo WK Immunocytochemical evidence that amyloid beta (1–42) impairs endogenous antioxidant systems in vivoNeuroscience2003 119399419
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65.
Borghi R Patriarca S Traverso N Piccini A Storace D Garuti A Gabriella C Patrizio O Massimo T The increased activity of BACE1 correlates with oxidative stress in Alzheimer's diseaseNeurobiol Aging2007 2810091014
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66.
Tong Y Zhou W Fung V Christensen MA Qing H Sun X Song W Oxidative stress potentiates BACE1 gene expression and Abeta generationJ Neural Transm2005 112455469
Not in our library10.1007/s00702-004-0255-3
67.
Tamagno E Bardini P Obbili A Vitali A Borghi R Zaccheo D Pronzato MA Danni O Smith MA Perry G Tabaton M Oxidative stress increases expression and activity of BACE in NT2 neuronsNeurobiol Dis2002 10279288
Not in our library10.1006/nbdi.2002.0515
68.
Paola D Domenicotti C Nitti M Vitali A Borghi R Cottalasso D Zaccheo D Odetti P Strocchi P Marinari UM Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cellsBiochem Biophys Res Commun2000 268642646
Not in our library10.1006/bbrc.2000.2164
69.
Tamagno E Parola M Bardini P Piccini A Borghi R Guglielmotto M Santoro G Davit A Danni O Smith MA Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathwaysJ Neurochem2005 92628636
Not in our library10.1111/j.1471-4159.2004.02895.x
70.
Mehan S Meena H Sharma D Sankhla R JNK: a stress-activated protein kinase therapeutic strategies and involvement in Alzheimer's and various neurodegenerative abnormalitiesJ Mol Neurosci2011 43376390
Not in our library10.1007/s12031-010-9454-6
71.
Yao M Nguyen TV Pike CJ Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-wJ Neurosci2005 2511491158
Not in our library10.1523/jneurosci.4736-04.2005
72.
Guglielmotto M Monteleone D Giliberto L Fornaro M Borghi R Tamagno E Tabaton M Amyloid-beta activates the expression of BACE1 through the JNK pathwayJ Alzheimers Dis2011 27871883
Not in our library10.3233/jad-2011-110884
73.
Zhu X Raina AK Rottkamp CA Aliev G Perry G Boux H Smith MA Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's diseaseJ Neurochem2001 76435441
Not in our library10.1046/j.1471-4159.2001.00046.x
74.
Tamagno E Parola M Guglielmotto M Santoro G Bardini P Marra L Tabaton M Danni O Multiple signaling events in amyloid beta-induced, oxidative stress-dependent neuronal apoptosisFree Radic Biol Med2003 354558
Not in our library10.1016/s0891-5849(03)00244-2
75.
Sastre M Klockgether T Heneka MT Contribution of inflammatory processes to Alzheimer's disease: molecular mechanismsInt J Dev Neurosci2006 24167176
Not in our library10.1016/j.ijdevneu.2005.11.014
76.
Tuppo EE Arias HR The role of inflammation in Alzheimer's diseaseInt J Biochem Cell Biol2005 37289305
Not in our library10.1016/j.biocel.2004.07.009
77.
Lynch MA Age-related neuroinflammatory changes negatively impact on neuronal functionFront Aging Neurosci2010 16
Not in our library10.3389/neuro.24.006.2009
78.
Eikelenboom P Veerhuis R The role of complement and activated microglia in the pathogenesis of Alzheimer's diseaseNeurobiol Aging1996 17673680
Not in our library10.1016/0197-4580(96)00108-x
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Akiyama H Barger S Barnum S Bradt B Bauer J Cole GM Cooper NR Eikelenboom P Emmerling M Fiebich BL Inflammation and Alzheimer's diseaseNeurobiol Aging2000 21383421
Not in our library10.1016/s0197-4580(00)00124-x
80.
Krause DL Muller N Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer's diseaseInt J Alzheimers Dis2010
Not in our library10.4061/2010/732806
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Wyss-Coray T Mucke L Inflammation in neurodegenerative disease–a double-edged swordNeuron2002 35419432
Not in our library10.1016/s0896-6273(02)00794-8
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Munch G Gasic-Milenkovic J Dukic-Stefanovic S Kuhla B Heinrich K Riederer P Huttunen HJ Founds H Sajithlal G Microglial activation induces cell death, inhibits neurite outgrowth and causes neurite retraction of differentiated neuroblastoma cellsExp Brain Res2003 15018
Not in our library10.1007/s00221-003-1389-5
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Meda L Cassatella MA Szendrei GI Otvos L Jr Baron P Villalba M Ferrari D Rossi F Activation of microglial cells by beta-amyloid protein and interferon-gammaNature1995 374647650
Not in our library10.1038/374647a0
84.
Johnstone M Gearing AJ Miller KM A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are producedJ Neuroimmunol1999 93182193
Not in our library10.1016/s0165-5728(98)00226-4
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Bamberger ME Harris ME McDonald DR Husemann J Landreth GE A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activationJ Neurosci2003 2326652674
Not in our library10.1523/jneurosci.23-07-02665.2003
86.
Yan SD Chen X Fu J Chen M Zhu H Roher A Slattery T Zhao L Nagashima M Morser J RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's diseaseNature1996 382685691
Not in our library10.1038/382685a0
87.
Rogers J Cooper NR Webster S Schultz J McGeer PL Styren SD Civin WH Brachova L Bradt B Ward P Complement activation by beta-amyloid in Alzheimer diseaseProc Natl Acad Sci USA1992 891001610020
Not in our library10.1073/pnas.89.21.10016
88.
Mercurio F Manning AM NF-kappaB as a primary regulator of the stress responseOncogene1999 1861636171
Not in our library10.1038/sj.onc.1203174
89.
Schreck R Rieber P Baeuerle PA Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1EMBO J1991 1022472258
Not in our library10.1002/j.1460-2075.1991.tb07761.x
90.
Clemens JA Stephenson DT Smalstig EB Dixon EP Little SP Global ischemia activates nuclear factor-kappa B in forebrain neurons of ratsStroke1997 2810731080discussion 1080–1071
Not in our library10.1161/01.str.28.5.1073
91.
Yang K Mu XS Hayes RL Increased cortical nuclear factor-kappa B (NF-kappa B) DNA binding activity after traumatic brain injury in ratsNeurosci Lett1995 197101104
Not in our library10.1016/0304-3940(95)11919-n
92.
Lawrence T The nuclear factor NF-kappaB pathway in inflammationCold Spring Harb Perspect Biol2009 1a001651
Not in our library10.1101/cshperspect.a001651
93.
Transcription factor NF-κB is activated in primary neurons by amyloid β peptides and in neurons surrounding early plaques from patients with Alzheimer disease · 1997
Not checked
94.
Inhibition of NF-κB potentiates amyloid β-mediated neuronal apoptosis · 1999
Not checked
95.
Terai K Matsuo A McGeer PL Enhancement of immunoreactivity for NF-kappa B in the hippocampal formation and cerebral cortex of Alzheimer's diseaseBrain Res1996 735159168
Not in our library10.1016/0006-8993(96)00310-1
96.
Barger SW Horster D Furukawa K Goodman Y Krieglstein J Mattson MP Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulationProc Natl Acad Sci USA1995 9293289332
Not in our library10.1073/pnas.92.20.9328
97.
Huang X Chen Y Zhang H Ma Q Zhang YW Xu H Salubrinal attenuates beta-amyloid-induced neuronal death and microglial activation by inhibition of the NF-kappaB pathwayNeurobiol Aging2011
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98.
Sheng JG Bora SH Xu G Borchelt DR Price DL Koliatsos VE Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic miceNeurobiol Dis2003 14133145
Not in our library10.1016/s0969-9961(03)00069-x
99.
Sambamurti K Kinsey R Maloney B Ge YW Lahiri DK Gene structure and organization of the human beta-secretase (BACE) promoterFASEB J2004 1810341036
Not in our library10.1096/fj.03-1378fje
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Chami L Buggia-Prevot V Duplan E Delprete D Chami M Peyron JF Checler F Nuclear factor-kappa B regulates betaAPP and beta- and gamma-secretases differently at physiological and supraphysiological Abeta concentrationsJ Biol Chem2012 2872457324584
Not in our library10.1074/jbc.m111.333054
101.
Sung S Yang H Uryu K Lee EB Zhao L Shineman D Trojanowski JQ Lee VM Pratico D Modulation of nuclear factor-kappa B activity by indomethacin influences A beta levels but not A beta precursor protein metabolism in a model of Alzheimer's diseaseAm J Pathol2004 16521972206
Not in our library10.1016/s0002-9440(10)63269-5
102.
Reduction of β-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease · 2010
No notice
103.
Choi DY Lee JW Lin G Lee YK Lee YH Choi IS Han SB Jung JK Kim YH Kim KH Obovatol attenuates LPS-induced memory impairments in mice via inhibition of NF-kappaB signaling pathwayNeurochem Int2011
Not in our library10.1016/j.neuint.2011.11.005
104.
He P Zhong Z Lindholm K Berning L Lee W Lemere C Staufenbiel M Li R Shen Y Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's miceJ Cell Biol2007 178829841
Not in our library10.1083/jcb.200705042
105.
Guglielmotto M Aragno M Tamagno E Vercellinatto I Visentin S Medana C Catalano MG Smith MA Perry G Danni O AGEs/RAGE complex upregulates BACE1 via NF-kappaB pathway activationNeurobiol Aging2010 33196 e113127
Not in our library10.1016/j.neurobiolaging.2010.05.026
106.
Heneka MT Landreth GE PPARs in the brainBiochim Biophys Acta2007 177110311045
Not in our library10.1016/j.bbalip.2007.04.016
107.
Sastre M Dewachter I Landreth GE Willson TM Klockgether T van Leuven F Heneka MT Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretaseJ Neurosci2003 2397969804
Not in our library10.1523/jneurosci.23-30-09796.2003
108.
Heneka MT Sastre M Dumitrescu-Ozimek L Hanke A Dewachter I Kuiperi C O'Banion K Klockgether T Van Leuven F Landreth GE Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic miceBrain2005 12814421453
Not in our library10.1093/brain/awh452
109.
D'Abramo C Massone S Zingg JM Pizzuti A Marambaud P Dalla Piccola B Azzi A Marinari UM Pronzato MA Ricciarelli R Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell deathBiochem J2005 391693698
Not in our library10.1042/bj20050560
110.
Gong B Chen F Pan Y Arrieta-Cruz I Yoshida Y Haroutunian V Pasinetti GM SCF(Fbx2) -E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic functionAging Cell2010 910181031
Not in our library10.1111/j.1474-9726.2010.00632.x
111.
Cho HJ Kim SK Jin SM Hwang EM Kim YS Huh K Mook-Jung I IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytesGlia2007 55253262
Not in our library10.1002/glia.20451
112.
The contribution of activated astrocytes to Aβ production: Implications for Alzheimer's disease pathogenesis · 2011
No notice
113.
Amara FM Junaid A Clough RR Liang B TGF-beta(1), regulation of alzheimer amyloid precursor protein mRNA expression in a normal human astrocyte cell line: mRNA stabilizationBrain Res Mol Brain Res1999 714249
Not in our library10.1016/s0169-328x(99)00158-8
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Rogers JT Leiter LM McPhee J Cahill CM Zhan SS Potter H Nilsson LN Translation of the alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequencesJ Biol Chem1999 27464216431
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Rossner S Lange-Dohna C Zeitschel U Perez-Polo JR Alzheimer's disease beta-secretase BACE1 is not a neuron-specific enzymeJ Neurochem2005 92226234
Not in our library10.1111/j.1471-4159.2004.02857.x
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Hartlage-Rubsamen M Zeitschel U Apelt J Gartner U Franke H Stahl T Gunther A Schliebs R Penkowa M Bigl V Rossner S Astrocytic expression of the Alzheimer's disease beta-secretase (BACE1) is stimulus-dependentGlia2003 41169179
Not in our library10.1002/glia.10178
117.
Bettegazzi B Mihailovich M Di Cesare A Consonni A Macco R Pelizzoni I Codazzi F Grohovaz F Zacchetti D beta-Secretase activity in rat astrocytes: translational block of BACE1 and modulation of BACE2 expressionEur J Neurosci2011
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118.
Kihara T Shimmyo Y Akaike A Niidome T Sugimoto H Abeta-induced BACE-1 cleaves N-terminal sequence of mPGES-2Biochem Biophys Res Commun2010 393728733
Not in our library10.1016/j.bbrc.2010.02.069
119.
Berridge MJ Bootman MD Lipp P Calcium–a life and death signalNature1998 395645648
Not in our library10.1038/27094
120.
Small DH Gasperini R Vincent AJ Hung AC Foa L The role of Abeta-induced calcium dysregulation in the pathogenesis of Alzheimer's diseaseJ Alzheimers Dis2009 16225233
Not in our library10.3233/jad-2009-0951
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Berridge MJ Calcium hypothesis of Alzheimer's diseasePflugers Arch2009 459441449
Not in our library10.1007/s00424-009-0736-1
122.
Bezprozvanny I Mattson MP Neuronal calcium mishandling and the pathogenesis of Alzheimer's diseaseTrends Neurosci2008 31454463
Not in our library10.1016/j.tins.2008.06.005
123.
Gibson GE Karuppagounder SS Shi Q Oxidant-induced changes in mitochondria and calcium dynamics in the pathophysiology of Alzheimer's diseaseAnn N Y Acad Sci2008 1147221232
Not in our library10.1196/annals.1427.038
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Dreses-Werringloer U Lambert JC Vingtdeux V Zhao H Vais H Siebert A Jain A Koppel J Rovelet-Lecrux A Hannequin D A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease riskCell2008 13311491161
Not in our library10.1016/j.cell.2008.05.048
125.
Lambert JC Sleegers K Gonzalez-Perez A Ingelsson M Beecham GW Hiltunen M Combarros O Bullido MJ Brouwers N Bettens K The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis studyJ Alzheimers Dis2010 22247255
Not in our library10.3233/jad-2010-100933
126.
Alberdi E Sanchez-Gomez MV Cavaliere F Perez-Samartin A Zugaza JL Trullas R Domercq M Matute C Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptorsCell Calcium2010 47264272
Not in our library10.1016/j.ceca.2009.12.010
127.
Lin H Bhatia R Lal R Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiologyFASEB J2001 1524332444
Not in our library10.1096/fj.01-0377com
128.
Synaptotoxicity of Alzheimer Beta Amyloid Can Be Explained by Its Membrane Perforating Property · 2010
No notice
129.
Chan SL Mayne M Holden CP Geiger JD Mattson MP Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neuronsJ Biol Chem2000 2751819518200
Not in our library10.1074/jbc.m000040200
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BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease · 2014
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