Open Access

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

Molecular Neurodegeneration20127:52

DOI: 10.1186/1750-1326-7-52

Received: 13 July 2012

Accepted: 3 October 2012

Published: 5 October 2012

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.

Keywords

Alzheimer’s disease BACE1 Inflammation Oxidative stress Calcium

The amyloid beta peptides

Alzheimer’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 [1]. Several risk factors such as aging, brain insults (stroke, traumatic injury), cardiovascular diseases (hypertension), or metabolic diseases (diabetes mellitus, hypercholesterolemia, obesity) [2] as well as genetic risk factors [3] have been identified but the etiology of the disease is far from being fully understood.

Aβ peptides composing the core of senile plaques are mainly produced by neuronal cells [4] 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 [5].

Even 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 [6]. 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 [7]. All these mutations modulate the endogenous levels or nature of Aβ peptides [5]. 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 [8].

Various 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 [9, 10]. 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 [11, 12]. 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.

In 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 [13]. Neprilysin mRNA and proteins are reduced in brain areas vulnerable to amyloid deposits [14] as is neprilysin activity in AD brains [15].

βAPP and its proteolytic fragments are involved in complex networks and several feedback loops have been suggested [16]. 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 [17]. 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 [18, 19]. 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

BACE1 (Asp2, memapsin 2), a single transmembrane aspartyl-protease, was identified in 1999 as the major β-secretase-like protein [2024]. Thus, brains and primary cortical cultures derived from BACE1 knock-out mice [2527] are devoid of β-secretase-like activity and do not produce Aβ. BACE1 is mainly expressed in neurons and in reactive astrocytes [4], in the Golgi apparatus and endosomes of cells, where amyloid peptides are mainly produced [28]. β-cleavage of βAPP is the rate-limiting step in Aβ generation [28] 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 [29]. BACE1 knockout mice are viable and fertile [25] but recent data indicate that these mice could harbor axon hypomyelination [30, 31], schizophrenia-like [32] and epileptic-like [33] behaviors.

Environmental [34, 35] and cellular [36] stresses induce the expression of BACE1. BACE1 promoter harbors functional binding sites for numerous transcription factors including specificity protein 1 (Sp1; [37]), Yin Yang 1 (YY1; [38]), the peroxisome proliferator-activated receptor γ (PPARγ [39]), the nuclear factor-κB (NF-κB; [40, 41]), the hypoxia-inducible factor 1(HIF-1; [42]), and signal transducer and activator of transcription 3 (STAT3; [43]). BACE1 activity increases with age [44] and pathology. In AD brains, BACE1 is elevated in regions that develop amyloid plaques and more particularly, in neurons surrounding amyloid plaques [41, 45, 46]. 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 [29, 4749].

As 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, [5053], a positive regulatory loop setting a vicious cycle can be delineated and is described in details below.

Oxidative stress

Oxidative stress in AD

Reactive 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 [54]. Oxidative damage further impairs the antioxidant defense and maintains oxidative burden in the cells [2, 54].

Lifespan accumulation of free radicals results in age-associated oxidative stress, the damages of which cause cellular and organism senescence [2, 55]. Oxidative stress is associated to AD as an early event [5658]. Oxidative stress contributes to AD; various mechanisms have been identified [59], such as the oxidative inactivation of the peptidyl-prolyl cis/trans isomerase 1 (Pin1) that affects its regulation of βAPP production and tau dephosphorylation [60]. 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 [54, 61]).

Aβ generates oxidative stress

Aβ peptides trigger oxidative stress in vitro and in vivo (reviewed by [59]). 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 [62, 63], and prefibrillar and oligomeric forms of Aβ1-42 induced higher oxidative stress than fibrillar Aβ1-42 in neuronal cells [50]. 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 [64].

Oxidative stress activates BACE1

BACE1 activity is positively correlated to oxidative stress markers in AD brains [65]. Treatment of cells with various oxidants increases BACE1 transcription, expression and activity [66, 67]. Oxidative stress regulates the γ-secretase activity as well [51], and treated cells produce more Aβ peptides [68, 69].

The JNK pathway is activated in response to oxidative stress, inflammatory cytokines and excitotoxic stimuli; then activated JNK positively regulates inflammation and apoptosis [70]. JNK is activated by Aβ in neuronal cultures [71, 72] and high levels of activated JNK have been reported in degenerating neurons of human AD brains [73] or transgenic mice [72]. JNK pathway also contributes to Aβ toxicity in vitro [71, 74] and production. Thus JNK gene manipulation or pharmacological blockade prevented oxidative stress-induced upregulation of BACE1 in mouse fibroblasts as well as in mice [51]. 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

As 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 [72]. Therefore, by inducing oxidative stress and activation of BACE1, Aβ regulates its own production (Figure 1).
https://static-content.springer.com/image/art%3A10.1186%2F1750-1326-7-52/MediaObjects/13024_2012_Article_368_Fig1_HTML.jpg
Figure 1

Oxidative stress mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides trigger oxidative stress by inducing ROS generation and impairing the antioxidant system. Oxidative stress and inflammatory cytokines activates JNK, then its transcription factor AP-1 upregulates BACE1. As BACE1 produces Aβ peptides, a vicious cycle is established. Aβ, amyloid peptide; AP-1, activator protein-1; BACE1, β-secretase βAPP cleaving enzyme 1; JNK, c-Jun N-terminal kinases; ROS, reactive oxygen species.

Inflammation

Inflammation in AD

In 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 [75]. These signals activate astrocytes that undergo morphological and functional changes, and thus participate to the inflammatory process [75]. Neurons contribute to microglial activation by production of pro-inflammatory cytokines and complement proteins [76].

Neuroinflammation 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 [77]. Local and chronic neuroinflammation is a constant feature of AD, and is characterized by activated microglia and astrocytes surrounding amyloid plaques and neurofibrillary tangles [78]. Accordingly, elevated levels of cytokines are measured in AD brains [79]. 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 [80, 81]. 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 [80, 82]. 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

Aβ treatment induces an activation of microglial and astrocytic cells, leading to the release of inflammatory factors [75, 83, 84]. Aβ activate glial cells by direct binding to microglial cell surface receptors [85], such as the receptor for advanced glycation end products (RAGE, [86]), by direct activation of the complement system [87], or by generating oxidative stress [88].

The transcription factor NF-κB is activated in response to various stresses [88]. NF-κB is induced by inflammation- and oxidative stress-linked conditions such as release of cytokines [88] and ROS [89], as well as ischemia [90] or traumatic brain injury [91] 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 [92].

Aβ peptides activate NF-κB in neurons and astrocytes [17, 93, 94]. The lowest Aβ concentrations were the more efficient to activate NF-κB [93, 94]. NF-κB activation has been reported in human cortex areas affected by the pathology, particularly in cells surrounding senile plaques [41, 9395]. The role of NF-κB activation remains unclear. Several works suggested a protective cellular response to Aβ-induced cell death [94, 96]. However other studies indicated that NF-κB could contribute to Aβ-associated toxicity, as inhibition of NF-κB reduced Aβ-induced neuronal death [17, 97].

Inflammation activates BACE1

The well-known inflammation inducer lipopolysaccharide (LPS) increases βAPP expression and processing in Swedish-βAPP transgenic mice [98]. LPS and inflammation activate the transcription factor NF-κB, for which BACE1 promoter harbors a highly conserved binding site [99] that is functional [40, 41]. NF-κB physiologically represses BACE1 transcription in vitro [40, 100], therefore limiting Aβ production.

However 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 [40, 41, 52, 100]. In vivo, the modulation of NF-κB activity by non-steroidal anti-inflammatory drugs [101], natural compounds [102, 103] or by targeting upstream receptors of the NF-κB activation pathway [58, 104], all affect Aβ production. In transgenic mice NF-κB activates βAPP levels [103], BACE1 promoter activity [104], expression [102, 105] and enzymatic activity [102, 103] as well as γ-secretase activity [103] and Aβ production [101103].

NF-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 [40, 100]. This could be explained by the activation of different NF-κB heterodimers yielded in a stimulus-dependent manner [40] even if this remains to be definitely established.

Other 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, [106]). 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 [39, 107, 108]. PPARγ agonists have additional beneficial effects on Aβ peptides production by increasing βAPP or BACE1 degradation [109, 110].

Prolonged 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 [38, 40, 111115] that are observed in the vicinity of amyloid plaques in both aged Tg2576 mice and AD-affected brains [116]. 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 [117].

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

At 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 [17, 40, 52, 100]. 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 [118]. Therefore by inducing inflammation and NF-κB activation, Aβ could act on its own production (Figure 2).
https://static-content.springer.com/image/art%3A10.1186%2F1750-1326-7-52/MediaObjects/13024_2012_Article_368_Fig2_HTML.jpg
Figure 2

Inflammation mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides are pro-inflammatory. They activate microglia and astrocytes that release inflammatory mediators. Those activate NF-κB, which is also activated by oxidative stress, ischemia or traumatic brain injury. Pathological activation of NF-κB activates BACE1 transcription, thus increasing Aβ peptides levels and feeding a vicious cycle. Aβ, amyloid peptide; BACE1, β-secretase βAPP cleaving enzyme 1; NF-κB, nuclear factor-κB.

Calcium homeostasis perturbation

Calcium signaling perturbation in AD

Calcium is a major signaling molecule involved in a variety of neuronal functions, such as neurotransmission, synaptic plasticity, excitotoxicity or apoptosis [119, 120]. Aging affects calcium sensitivity and homeostasis, thereby triggering neuronal vulnerability and cell death. Oxidative stress is tightly associated to these calcium homeostasis alterations [121, 122].

The 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 [121, 123]. 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 [121]. 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 [124]. 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 [125].

Aβ affects cellular calcium homeostasis

Calcium homeostasis disturbance is part of Aβ neurotoxicity (for reviews see [120122]). 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 [126]. Aβ could impair the intracellular distribution of calcium by perforating and permeabilizing the membrane to calcium via oxidative stress [120, 127, 128]. Noteworthy, some presenilin mutations responsible for familial AD and yielding enhanced Aβ levels, impair calcium homeostasis by deregulating internal calcium channels ryanodine receptor [129], inositol 1,4,5-triphosphate (IP3) channel [130] or sarco endoplasmic reticulum calcium ATPase (SERCA; [131]). 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 [132]. 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 [133] involved in the transactivation of genes related to AD [134, 135]. Similarly, AICD is involved in calcium signaling [136] or homeostasis in different cell culture models [137].

Calcium disturbance activates BACE1

Calcium dysregulation promotes tau phosphorylation and Aβ accumulation in neuronal cells [138140]. Calpain is an intracellular cystein protease regulated by calcium and abnormally activated in AD brains [141, 142]. In transgenic mice brains, calpain over-activation induces amyloid deposits, tau phosphorylation, activation of astrocytes, synapse loss and cognitive impairment [141, 143]. Furthermore, βAPP processing is affected as βAPP C-terminal fragments are decreased following calpain inhibition in these mice [143].

BACE1 upregulation could be mediated by cyclin-dependent kinase 5 (cdk5), which is regulated by calpain [144]. Cdk5 activates BACE1 promoter by binding of its target STAT3, therefore increasing BACE1 activity, Aβ1-40 and Aβ1-42 production in transgenic mice [43]. 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 [145], translocates to the nucleus, binds to BACE1 promoter, activates its transcription and increases Aβ generation, as demonstrated in vitro [145].

Many 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 [146]. Similar results were obtained on Aβ production using thapsigargin, a pharmacological raiser of cytoplasmic calcium levels [147].

Aβ peptides regulate BACE1 via calcium-dependent pathways

As 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 [145, 148] and increased BACE1 expression [143, 145] that was reduced by calpain inhibition [143] or calcineurin-mediated NFAT1 inhibition [145]. Therefore calcium is another intermediate by which Aβ upregulates BACE1, and thus its own production (Figure 3).
https://static-content.springer.com/image/art%3A10.1186%2F1750-1326-7-52/MediaObjects/13024_2012_Article_368_Fig3_HTML.jpg
Figure 3

Disturbed calcium homeostasis mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides increase cytoplasmic calcium by at least three mechanisms: stimulation of membrane ion channels or receptors; permeabilization of the membrane; and deregulation of internal calcium channels. Presenilins mutations contribute to the latter. Increased calcium then activates the calpain/cdk5/STAT3 pathway and NFAT1. The transcription factors STAT3 and NFAT1 upregulate BACE1, which then produces more Aβ peptides and a positive feedback mechanism is set up. Aβ, amyloid peptide; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; IP3, inositol 1,4,5-triphosphate; NFAT1, nuclear factor of activated T-cells 1; SERCA, sarco endoplasmic reticulum calcium ATPase; STAT, signal transducer and activator of transcription.

Advanced glycation end (AGE) products

AGEs in AD

AGEs 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 [149]. AGEs accumulate in aged tissue and contribute to the age-related deterioration of cellular functions [150]. AGE production can be enhanced in pathological contexts such as diabetes mellitus-associated hyperglycemia, inflammation, and hypoxia [149, 151]. AGEs pathogenicity is linked to the concomitant oxidative stress generated during their formation, to their interaction with its receptor RAGE [152], or by the accumulation of non-degradable proteins [149, 151]. Furthermore, AGEs binding to RAGE intensifies inflammation by activation of NF-κB and by release of pro-inflammatory cytokines [153, 154]. In turn, NF-κB transactivates RAGE promoter [155]. Finally, AGEs compete with other physiological ligands interacting with RAGE, such as growth or differentiation factors [149, 151].

Cerebral levels of AGEs are increased in human AD brains, especially in neurofibrillary tangles and amyloid deposits [156159]. 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 [160], and AGEs favor Aβ peptides aggregation [157, 161].

Aβ modulates the AGE/RAGE signaling cascade

Aβ peptides that can be considered as AGEs, bind to RAGE [86] 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 [162]. 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 [163].

AGEs and RAGE activate BACE1

AGEs can influence Aβ generation. AGEs induce βAPP expression by generating oxidative stress in SH-SY5Y cells [164] and in transgenic mice model of AD, RAGE injection increases Aβ accumulation and senile plaques [165]. 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 [165]. 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 [165]. 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 [166]. Therefore, RAGE activation by AGEs or Aβ activate BACE1 transcription and thereby, increases Aβ production (Figure 4).
https://static-content.springer.com/image/art%3A10.1186%2F1750-1326-7-52/MediaObjects/13024_2012_Article_368_Fig4_HTML.jpg
Figure 4

Aβ and AGEs activate BACE1 transcription. Aβ peptides activate RAGE. This receptor is also activated by AGEs produced during diabetes mellitus, inflammation or hypoxia. RAGE activation upregulates BACE1 by the activation of the two transcription factors NF-κB and NFAT1. Additionally, AGEs can activate BACE1 by generating oxidative stress. BACE1 contribution to Aβ peptides production then amplifies RAGE activation. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; NFAT1, nuclear factor of activated T-cells 1; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end products.

Brain insults

Traumatic brain injury

Traumatic brain injury is a risk factor for AD [167]. Post mortem analysis of patients who had traumatic brain injury revealed deposition of Aβ peptides in brain and abnormal distribution in the cerebrospinal fluid [167, 168]. This was confirmed in transgenic mice model of AD, where repetitive traumatic brain injury triggered Aβ accumulation [169]. Traumatic brain injury is followed by an increase of BACE1 mRNA, protein and activity, as well as an accumulation of βAPP and presenilin 1 [170172].

BACE1 activation could be due to oxidative stress and NF-κB activation following traumatic brain injury [91, 169, 173], 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 [174176]. Following head injury, activated caspases cleave GGA1 and GGA3, thereby stabilizing BACE1 [177].
https://static-content.springer.com/image/art%3A10.1186%2F1750-1326-7-52/MediaObjects/13024_2012_Article_368_Fig5_HTML.jpg
Figure 5

Traumatic brain injury contributes to Aβ deposition by activating BACE1 transcription. Traumatic brain injury activates BACE1 by inducing oxidative stress and by activating the NF-κB transcription factor. This leads to Aβ deposition. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; NF-κB, nuclear factor-κB.

BACE1 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 [172].

Hypoxia

Vascular risk factors, like heart disease or stroke leading to hypoperfusion are risk factors for AD [178, 179]. 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 [180].

In 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 [42, 181]. Guglielmotto and collaborators [182] 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 [182], other hypoxia-linked mechanisms could contribute to BACE1 activation, such as the activation of calpain and cdk5 [183185], or the upregulation of RAGE or NF-κB by an HIF-1α-dependent transcriptional activation [186189]. The three mechanisms explaining hypoxia-induced BACE1 upregulation are summarized in Figure 6.
https://static-content.springer.com/image/art%3A10.1186%2F1750-1326-7-52/MediaObjects/13024_2012_Article_368_Fig6_HTML.jpg
Figure 6

Hypoxia contributes to Aβ deposition by activating BACE1 transcription. Hypoxia activates BACE1 by three distinct mechanisms: generation of oxidative stress and the subsequent activation of the JNK pathway; activation of HIF-1 transcription factor which activates BACE1 promoter directly or indirectly through the activation of NF-κB and RAGE; activation of calpain and cdk5 resulting from increased calcium concentrations. By activating BACE1 transcription, hypoxia thus leads to Aβ deposition. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; HIF-1, hypoxia-inducible factor 1; JNK, c-Jun N-terminal kinases; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end products.

Finally, two additional post-transcriptional mechanisms contribute to elevate BACE1 levels: the phosphorylation of eIF2α subsequent to energy deprivation that translationally activates BACE1 [190]; reduction of GGA3 levels following ischemia, leading to BACE1 stabilization and increased β-secretase activity [191].

Aβ-linked apoptosis in AD

Aβ 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 [11]). Aβ can directly induce apoptosis by activating the transcription of the tumor suppressor p53 [192], the expression of which is increased in AD brains [192, 193]. Furthermore, by activating p53, Aβ and AICD can regulate their own production [192, 194196], 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) [195, 197, 198].

Conclusion

Changes observed in AD brains are not necessarily causes of the disease, and could be consequences of the pathological process [199]. 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 [200], neuronal viability [201, 202], protection from glutamate and N-methyl-D-aspartic acid excitoxicities [202, 203], and reduction of oxidative damage [204206]. Aβ excess is considered to have a causative role in AD pathogenesis, but could be a protective mechanism in response to various stresses [9, 204, 207, 208].

Nevertheless, 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 [209].
https://static-content.springer.com/image/art%3A10.1186%2F1750-1326-7-52/MediaObjects/13024_2012_Article_368_Fig7_HTML.jpg
Figure 7

Cellular stress, BACE1 and Aβ production are involved in a toxic vicious cycle in AD. Various cellular dysfunctions including oxidative stress, inflammation and calcium homeostasis disturbance occur in AD-affected brains. These alterations activate the transcription of the stress-induced β-secretase BACE1 that contributes to Aβ production. Once yielded at supra-physiological levels, Aβ induces cellular stresses that, in turn activate BACE1, therefore setting up a vicious cycle. Such self-maintained toxicity can lead to cellular cell death. Brain insults like hypoxia and traumatic brain injury contribute to this scheme by inducing cellular stress.

Since 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 [210]). However BACE1 inhibition should not be complete to prevent potential side effects (hypomyelination, schizophrenia- and epileptic-like behaviors, hippocampal neurodegeneration [3033, 210]) 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 [211, 212]. 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 [211].

Abbreviations

Aβ: 

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

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.

Declarations

Acknowledgements

This work has been supported by the Fondation pour la Recherche Médicale (FRM), by the Conseil Général des Alpes Maritimes, and by the Ministère de l’enseignement supérieur et de la Recherche. This work has been developed and supported through the LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).

Authors’ Affiliations

(1)
Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA
(2)
Team labelized Fondation pour la Recherche Médicale
(3)
LABEX (Laboratory of Excellence)

References

  1. Querfurth HW, LaFerla FM: Alzheimer's disease. N Engl J Med. 2010, 362: 329-344.PubMed
  2. Kern A, Behl C: The unsolved relationship of brain aging and late-onset Alzheimer disease. Biochim Biophys Acta. 2009, 1790: 1124-1132.PubMed
  3. Lambert JC, Amouyel P: Genetics of Alzheimer's disease: new evidences for an old hypothesis?. Curr Opin Genet Dev. 2011, 21: 295-301.PubMed
  4. Rossner S, Apelt J, Schliebs R, Perez-Polo JR, Bigl V: Neuronal and glial beta-secretase (BACE) protein expression in transgenic Tg2576 mice with amyloid plaque pathology. J Neurosci Res. 2001, 64: 437-446.PubMed
  5. Checler F: Processing of the beta-amyloid precursor protein and its regulation in Alzheimer's disease. J Neurochem. 1995, 65: 1431-1444.PubMed
  6. Suh YH, Checler F: Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol Rev. 2002, 54: 469-525.PubMed
  7. St George-Hyslop PH: Molecular genetics of Alzheimer's disease. Biol Psychiatry. 2000, 47: 183-199.PubMed
  8. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, et al: A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012, 488: 96-9.PubMed
  9. Sevalle J, Amoyel A, Robert P, Fournie-Zaluski MC, Roques B, Checler F: Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide. J Neurochem. 2009, 109: 248-256.PubMed
  10. Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, Holzer M, Hutter-Paier B, Prokesch M, Windisch M, et al: Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology. Nat Med. 2008, 14: 1106-1111.PubMed
  11. Di Carlo M: Beta amyloid peptide: from different aggregation forms to the activation of different biochemical pathways. Eur Biophys J. 2010, 39: 877-888.PubMed
  12. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ: Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002, 416: 535-539.PubMed
  13. Wang DS, Dickson DW, Malter JS: beta-Amyloid degradation and Alzheimer's disease. J Biomed Biotechnol. 2006, 2006: 58406-PubMed CentralPubMed
  14. Yasojima K, Akiyama H, McGeer EG, McGeer PL: Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci Lett. 2001, 297: 97-100.PubMed
  15. Wang S, Wang R, Chen L, Bennett DA, Dickson DW, Wang DS: Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer's brain. J Neurochem. 2010, 115: 47-57.PubMed CentralPubMed
  16. Hunter S, Brayne C: Relationships between the amyloid precursor protein and its various proteolytic fragments and neuronal systems. Alzheimers Res Ther. 2012, 4: 10-PubMed CentralPubMed
  17. Valerio A, Boroni F, Benarese M, Sarnico I, Ghisi V, Bresciani LG, Ferrario M, Borsani G, Spano P, Pizzi M: NF-kappaB pathway: a target for preventing beta-amyloid (Abeta)-induced neuronal damage and Abeta42 production. Eur J Neurosci. 2006, 23: 1711-1720.PubMed
  18. 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 motif. Gene. 2011, 488: 1-12.PubMed CentralPubMed
  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 amyloidogenesis. Gene. 2011, 488: 13-22.PubMed CentralPubMed
  20. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, 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.PubMed
  21. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, et al: Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999, 402: 537-540.PubMed
  22. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, et al: Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999, 402: 533-537.PubMed
  23. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, et al: Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci. 1999, 14: 419-427.PubMed
  24. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J: Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA. 2000, 97: 1456-1460.PubMed CentralPubMed
  25. Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, et al: BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum Mol Genet. 2001, 10: 1317-1324.PubMed
  26. Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, et al: Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci. 2001, 4: 231-232.PubMed
  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 neurons. Nat Neurosci. 2001, 4: 233-234.PubMed
  28. Vassar R: The beta-secretase, BACE: a prime drug target for Alzheimer's disease. J Mol Neurosci. 2001, 17: 157-170.PubMed
  29. Cole SL, Vassar R: The Alzheimer's disease beta-secretase enzyme, BACE1. Mol Neurodegener. 2007, 2: 22-PubMed CentralPubMed
  30. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R: Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006, 9: 1520-1525.PubMed
  31. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C: Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006, 314: 664-666.PubMed
  32. 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 mice. Proc Natl Acad Sci USA. 2008, 105: 5585-5590.PubMed CentralPubMed
  33. Hu X, Zhou X, He W, Yang J, Xiong W, Wong P, Wilson CG, Yan R: BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci. 2010, 30: 8819-8829.PubMed CentralPubMed
  34. Devi L, Alldred MJ, Ginsberg SD, Ohno M: Sex- and brain region-specific acceleration of beta-amyloidogenesis following behavioral stress in a mouse model of Alzheimer's disease. Mol Brain. 2010, 3: 34-PubMed CentralPubMed
  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 proteases. Endocrinology. 2011, 152: 2704-2715.PubMed
  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 potential. J Neurosci. 2009, 29: 12787-12794.PubMed CentralPubMed
  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 Sp1. Mol Cell Biol. 2004, 24: 865-874.PubMed CentralPubMed
  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 expression. J Neurochem. 2006, 96: 1696-1707.PubMed
  39. Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, et al: Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci USA. 2006, 103: 443-448.PubMed CentralPubMed
  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 peptides. J Neurosci Res. 2007, 85: 1194-1204.PubMed
  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 disease. Int J Neuropsychopharmacol. 2011, 1-14.
  42. Zhang X, Zhou K, Wang R, Cui J, Lipton SA, Liao FF, Xu H, Zhang YW: Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J Biol Chem. 2007, 282: 10873-10880.PubMed
  43. Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marie I, Maurin T, Wang L, Figueroa H, Herman M, et al: Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008, 57: 680-690.PubMed CentralPubMed
  44. Fukumoto H, Rosene DL, Moss MB, Raju S, Hyman BT, Irizarry MC: Beta-secretase activity increases with aging in human, monkey, and mouse brain. Am J Pathol. 2004, 164: 719-725.PubMed CentralPubMed
  45. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC: Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol. 2002, 59: 1381-1389.PubMed
  46. Zhao J, Fu Y, Yasvoina M, Shao P, Hitt B, O'Connor T, Logan S, Maus E, Citron M, Berry R, et al: Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci. 2007, 27: 3639-3649.PubMed
  47. Rossner S, Sastre M, Bourne K, Lichtenthaler SF: Transcriptional and translational regulation of BACE1 expression–implications for Alzheimer's disease. Prog Neurobiol. 2006, 79: 95-111.PubMed
  48. Stockley JH, O'Neill C: Understanding BACE1: essential protease for amyloid-beta production in Alzheimer's disease. Cell Mol Life Sci. 2008, 65: 3265-3289.PubMed
  49. Wang JF, Lu R, Wang YZ: Regulation of beta cleavage of amyloid precursor protein. Neurosci Bull. 2010, 26: 417-427.PubMed
  50. Tamagno E, Bardini P, Guglielmotto M, Danni O, Tabaton M: The various aggregation states of beta-amyloid 1–42 mediate different effects on oxidative stress, neurodegeneration, and BACE-1 expression. Free Radic Biol Med. 2006, 41: 202-212.PubMed
  51. Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, Muraca G, Danni O, Zhu X, Smith MA, 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.PubMed CentralPubMed
  52. Buggia-Prevot V, Sevalle J, Rossner S, Checler F: NFkappaB-dependent control of BACE1 promoter transactivation by Abeta42. J Biol Chem. 2008, 283: 10037-10047.PubMed
  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 disease. J Biol Chem. 2012, 287: 7224-7235.PubMed CentralPubMed
  54. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J: Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007, 39: 44-84.PubMed
  55. Harman D: Free radicals in aging. Mol Cell Biochem. 1988, 84: 155-161.PubMed
  56. Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N: Oxidative damage in Alzheimer's. Nature. 1996, 382: 120-121.PubMed
  57. Behl C, Moosmann B: Antioxidant neuroprotection in Alzheimer's disease as preventive and therapeutic approach. Free Radic Biol Med. 2002, 33: 182-191.PubMed
  58. Guglielmotto M, Giliberto L, Tamagno E, Tabaton M: Oxidative stress mediates the pathogenic effect of different Alzheimer's disease risk factors. Front Aging Neurosci. 2010, 2: 3-PubMed CentralPubMed
  59. Sultana R, Butterfield DA: Role of Oxidative Stress in the Progression of Alzheimer's Disease. J Alzheimers Dis. 2009
  60. Butterfield DA, Abdul HM, Opii W, Newman SF, Joshi G, Ansari MA, Sultana R: Pin1 in Alzheimer's disease. J Neurochem. 2006, 98: 1697-1706.PubMed
  61. Castellani RJ, Lee HG, Perry G, Smith MA: Antioxidant protection and neurodegenerative disease: the role of amyloid-beta and tau. Am J Alzheimers Dis Other Demen. 2006, 21: 126-130.PubMed
  62. Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, et al: The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. 1999, 38: 7609-7616.PubMed
  63. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, et al: Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999, 274: 37111-37116.PubMed
  64. Kim HC, Yamada K, Nitta A, Olariu A, Tran MH, Mizuno M, Nakajima A, Nagai T, Kamei H, Jhoo WK, et al: Immunocytochemical evidence that amyloid beta (1–42) impairs endogenous antioxidant systems in vivo. Neuroscience. 2003, 119: 399-419.PubMed
  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 disease. Neurobiol Aging. 2007, 28: 1009-1014.PubMed
  66. Tong Y, Zhou W, Fung V, Christensen MA, Qing H, Sun X, Song W: Oxidative stress potentiates BACE1 gene expression and Abeta generation. J Neural Transm. 2005, 112: 455-469.PubMed
  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 neurons. Neurobiol Dis. 2002, 10: 279-288.PubMed
  68. Paola D, Domenicotti C, Nitti M, Vitali A, Borghi R, Cottalasso D, Zaccheo D, Odetti P, Strocchi P, Marinari UM, et al: Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem Biophys Res Commun. 2000, 268: 642-646.PubMed
  69. Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, 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.PubMed
  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 abnormalities. J Mol Neurosci. 2011, 43: 376-390.PubMed
  71. Yao M, Nguyen TV, Pike CJ: Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. J Neurosci. 2005, 25: 1149-1158.PubMed
  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 pathway. J Alzheimers Dis. 2011, 27: 871-883.PubMed
  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 disease. J Neurochem. 2001, 76: 435-441.PubMed
  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 apoptosis. Free Radic Biol Med. 2003, 35: 45-58.PubMed
  75. Sastre M, Klockgether T, Heneka MT: Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int J Dev Neurosci. 2006, 24: 167-176.PubMed
  76. Tuppo EE, Arias HR: The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol. 2005, 37: 289-305.PubMed
  77. Lynch MA: Age-related neuroinflammatory changes negatively impact on neuronal function. Front Aging Neurosci. 2010, 1: 6-PubMed CentralPubMed
  78. Eikelenboom P, Veerhuis R: The role of complement and activated microglia in the pathogenesis of Alzheimer's disease. Neurobiol Aging. 1996, 17: 673-680.PubMed
  79. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, et al: Inflammation and Alzheimer's disease. Neurobiol Aging. 2000, 21: 383-421.PubMed CentralPubMed
  80. Krause DL, Muller N: Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer's disease. Int J Alzheimers Dis. 2010
  81. Wyss-Coray T, Mucke L: Inflammation in neurodegenerative disease–a double-edged sword. Neuron. 2002, 35: 419-432.PubMed
  82. 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 cells. Exp Brain Res. 2003, 150: 1-8.PubMed
  83. Meda L, Cassatella MA, Szendrei GI, Otvos L, Baron P, Villalba M, Ferrari D, Rossi F: Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature. 1995, 374: 647-650.PubMed
  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 produced. J Neuroimmunol. 1999, 93: 182-193.PubMed
  85. Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE: A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci. 2003, 23: 2665-2674.PubMed
  86. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, et al: RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature. 1996, 382: 685-691.PubMed
  87. Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, Civin WH, Brachova L, Bradt B, Ward P, et al: Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci USA. 1992, 89: 10016-10020.PubMed CentralPubMed
  88. Mercurio F, Manning AM: NF-kappaB as a primary regulator of the stress response. Oncogene. 1999, 18: 6163-6171.PubMed
  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-1. EMBO J. 1991, 10: 2247-2258.PubMed CentralPubMed
  90. Clemens JA, Stephenson DT, Smalstig EB, Dixon EP, Little SP: Global ischemia activates nuclear factor-kappa B in forebrain neurons of rats. Stroke. 1997, 28: 1073-1080. discussion 1080–1071PubMed
  91. Yang K, Mu XS, Hayes RL: Increased cortical nuclear factor-kappa B (NF-kappa B) DNA binding activity after traumatic brain injury in rats. Neurosci Lett. 1995, 197: 101-104.PubMed
  92. Lawrence T: The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009, 1: a001651-PubMed CentralPubMed
  93. Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C: Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc Natl Acad Sci USA. 1997, 94: 2642-2647.PubMed CentralPubMed
  94. Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C: Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis. Proc Natl Acad Sci USA. 1999, 96: 9409-9414.PubMed CentralPubMed
  95. Terai K, Matsuo A, McGeer PL: Enhancement of immunoreactivity for NF-kappa B in the hippocampal formation and cerebral cortex of Alzheimer's disease. Brain Res. 1996, 735: 159-168.PubMed
  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+ accumulation. Proc Natl Acad Sci USA. 1995, 92: 9328-9332.PubMed CentralPubMed
  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 pathway. Neurobiol Aging. 2011
  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 mice. Neurobiol Dis. 2003, 14: 133-145.PubMed
  99. Sambamurti K, Kinsey R, Maloney B, Ge YW, Lahiri DK: Gene structure and organization of the human beta-secretase (BACE) promoter. FASEB J. 2004, 18: 1034-1036.PubMed
  100. 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 concentrations. J Biol Chem. 2012, 287: 24573-24584.PubMed CentralPubMed
  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 disease. Am J Pathol. 2004, 165: 2197-2206.PubMed CentralPubMed
  102. Paris D, Ganey NJ, Laporte V, Patel NS, Beaulieu-Abdelahad D, Bachmeier C, March A, Ait-Ghezala G, Mullan MJ: Reduction of beta-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation. 2010, 7: 17-PubMed CentralPubMed
  103. Choi DY, Lee JW, Lin G, Lee YK, Lee YH, Choi IS, Han SB, Jung JK, Kim YH, Kim KH, et al: Obovatol attenuates LPS-induced memory impairments in mice via inhibition of NF-kappaB signaling pathway. Neurochem Int. 2011
  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 mice. J Cell Biol. 2007, 178: 829-841.PubMed CentralPubMed
  105. Guglielmotto M, Aragno M, Tamagno E, Vercellinatto I, Visentin S, Medana C, Catalano MG, Smith MA, Perry G, Danni O, et al: AGEs/RAGE complex upregulates BACE1 via NF-kappaB pathway activation. Neurobiol Aging. 2010, 33 (196 e): 113-127.
  106. Heneka MT, Landreth GE: PPARs in the brain. Biochim Biophys Acta. 2007, 1771: 1031-1045.PubMed
  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-secretase. J Neurosci. 2003, 23: 9796-9804.PubMed
  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 mice. Brain. 2005, 128: 1442-1453.PubMed
  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 death. Biochem J. 2005, 391: 693-698.PubMed CentralPubMed
  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 function. Aging Cell. 2010, 9: 1018-1031.PubMed CentralPubMed
  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 astrocytes. Glia. 2007, 55: 253-262.PubMed
  112. Zhao J, O'Connor T, Vassar R: The contribution of activated astrocytes to Abeta production: Implications for Alzheimer's disease pathogenesis. J Neuroinflammation. 2011, 8: 150-PubMed CentralPubMed
  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 stabilization. Brain Res Mol Brain Res. 1999, 71: 42-49.PubMed
  114. 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 sequences. J Biol Chem. 1999, 274: 6421-6431.PubMed
  115. Rossner S, Lange-Dohna C, Zeitschel U, Perez-Polo JR: Alzheimer's disease beta-secretase BACE1 is not a neuron-specific enzyme. J Neurochem. 2005, 92: 226-234.PubMed
  116. 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-dependent. Glia. 2003, 41: 169-179.PubMed
  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 expression. Eur J Neurosci. 2011
  118. Kihara T, Shimmyo Y, Akaike A, Niidome T, Sugimoto H: Abeta-induced BACE-1 cleaves N-terminal sequence of mPGES-2. Biochem Biophys Res Commun. 2010, 393: 728-733.PubMed
  119. Berridge MJ, Bootman MD, Lipp P: Calcium–a life and death signal. Nature. 1998, 395: 645-648.PubMed
  120. Small DH, Gasperini R, Vincent AJ, Hung AC, Foa L: The role of Abeta-induced calcium dysregulation in the pathogenesis of Alzheimer's disease. J Alzheimers Dis. 2009, 16: 225-233.PubMed
  121. Berridge MJ: Calcium hypothesis of Alzheimer's disease. Pflugers Arch. 2009, 459: 441-449.PubMed
  122. Bezprozvanny I, Mattson MP: Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 2008, 31: 454-463.PubMed CentralPubMed
  123. Gibson GE, Karuppagounder SS, Shi Q: Oxidant-induced changes in mitochondria and calcium dynamics in the pathophysiology of Alzheimer's disease. Ann N Y Acad Sci. 2008, 1147: 221-232.PubMed CentralPubMed
  124. Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, et al: A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell. 2008, 133: 1149-1161.PubMed CentralPubMed
  125. Lambert JC, Sleegers K, Gonzalez-Perez A, Ingelsson M, Beecham GW, Hiltunen M, Combarros O, Bullido MJ, Brouwers N, Bettens K, et al: The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study. J Alzheimers Dis. 2010, 22: 247-255.PubMed CentralPubMed
  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 receptors. Cell Calcium. 2010, 47: 264-272.PubMed
  127. Lin H, Bhatia R, Lal R: Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology. FASEB J. 2001, 15: 2433-2444.PubMed
  128. Sepulveda FJ, Parodi J, Peoples RW, Opazo C, Aguayo LG: Synaptotoxicity of Alzheimer beta amyloid can be explained by its membrane perforating property. PLoS One. 2010, 5: e11820-PubMed CentralPubMed
  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 neurons. J Biol Chem. 2000, 275: 18195-18200.PubMed
  130. Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK: Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron. 2008, 58: 871-883.PubMed CentralPubMed
  131. Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM: SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol. 2008, 181: 1107-1116.PubMed CentralPubMed
  132. Oulès B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, Moreno S, Paterlini-Bréchot P, Trebak M, Checler F, et al: Ryanodine receptors blockade reduces Amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci. 2012, 32: 11820-11834.PubMed CentralPubMed
  133. Cao X, Sudhof TC: A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001, 293: 115-120.PubMed
  134. Muller T, Meyer HE, Egensperger R, Marcus K: The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-relevance for Alzheimer's disease. Prog Neurobiol. 2008, 85: 393-406.PubMed
  135. Pardossi-Piquard R, Checler F: The physiology of the beta-amyloid precursor protein intracellular domain AICD. J Neurochem. 2012, 120 (Suppl 1): 109-124.PubMed
  136. Leissring MA, Murphy MP, Mead TR, Akbari Y, Sugarman MC, Jannatipour M, Anliker B, Muller U, Saftig P, De Strooper B, et al: A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP. Proc Natl Acad Sci USA. 2002, 99: 4697-4702.PubMed CentralPubMed
  137. Hamid R, Kilger E, Willem M, Vassallo N, Kostka M, Bornhovd C, Reichert AS, Kretzschmar HA, Haass C, Herms J: Amyloid precursor protein intracellular domain modulates cellular calcium homeostasis and ATP content. J Neurochem. 2007, 102: 1264-1275.PubMed
  138. Querfurth HW, Selkoe DJ: Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry. 1994, 33: 4550-4561.PubMed
  139. Pierrot N, Santos SF, Feyt C, Morel M, Brion JP, Octave JN: Calcium-mediated transient phosphorylation of tau and amyloid precursor protein followed by intraneuronal amyloid-beta accumulation. J Biol Chem. 2006, 281: 39907-39914.PubMed
  140. Mattson MP: Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons. Neuron. 1990, 4: 105-117.PubMed
  141. Higuchi M, Iwata N, Matsuba Y, Takano J, Suemoto T, Maeda J, Ji B, Ono M, Staufenbiel M, Suhara T, Saido TC: Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology. FASEB J. 2012, 26: 1204-1217.PubMed
  142. Liu F, Grundke-Iqbal I, Iqbal K, Oda Y, Tomizawa K, Gong CX: Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem. 2005, 280: 37755-37762.PubMed
  143. Liang B, Duan BY, Zhou XP, Gong JX, Luo ZG: Calpain activation promotes BACE1 expression, amyloid precursor protein processing, and amyloid plaque formation in a transgenic mouse model of Alzheimer disease. J Biol Chem. 2010, 285: 27737-27744.PubMed CentralPubMed
  144. Kusakawa G, Saito T, Onuki R, Ishiguro K, Kishimoto T, Hisanaga S: Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25. J Biol Chem. 2000, 275: 17166-17172.PubMed
  145. Cho HJ, Jin SM, Youn HD, Huh K, Mook-Jung I: Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling. Aging Cell. 2008, 7: 137-147.PubMed
  146. Hayley M, Perspicace S, Schulthess T, Seelig J: Calcium enhances the proteolytic activity of BACE1: An in vitro biophysical and biochemical characterization of the BACE1-calcium interaction. Biochim Biophys Acta. 2009, 1788: 1933-1938.PubMed
  147. Buxbaum JD, Ruefli AA, Parker CA, Cypess AM, Greengard P: Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Proc Natl Acad Sci USA. 1994, 91: 4489-4493.PubMed CentralPubMed
  148. Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH: Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature. 2000, 405: 360-364.PubMed
  149. Munch G, Thome J, Foley P, Schinzel R, Riederer P: Advanced glycation endproducts in ageing and Alzheimer's disease. Brain Res Brain Res Rev. 1997, 23: 134-143.PubMed
  150. Li JJ, Surini M, Catsicas S, Kawashima E, Bouras C: Age-dependent accumulation of advanced glycosylation end products in human neurons. Neurobiol Aging. 1995, 16: 69-76.PubMed
  151. Ramasamy R, Yan SF, Schmidt AM: Advanced glycation endproducts: from precursors to RAGE: round and round we go. Amino Acids. 2010
  152. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A: Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem. 1992, 267: 14998-15004.PubMed
  153. Yan SD, Yan SF, Chen X, Fu J, Chen M, Kuppusamy P, Smith MA, Perry G, Godman GC, Nawroth P, et al: Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med. 1995, 1: 693-699.PubMed
  154. Neumann A, Schinzel R, Palm D, Riederer P, Munch G: High molecular weight hyaluronic acid inhibits advanced glycation endproduct-induced NF-kappaB activation and cytokine expression. FEBS Lett. 1999, 453: 283-287.PubMed
  155. Li J, Schmidt AM: Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem. 1997, 272: 16498-16506.PubMed
  156. Smith MA, Taneda S, Richey PL, Miyata S, Yan SD, Stern D, Sayre LM, Monnier VM, Perry G: Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci USA. 1994, 91: 5710-5714.PubMed CentralPubMed
  157. Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A: Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA. 1994, 91: 4766-4770.PubMed CentralPubMed
  158. Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW, Caputo C, Frappier T, Smith MA, et al: Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA. 1994, 91: 7787-7791.PubMed CentralPubMed
  159. Dickson DW, Sinicropi S, Yen SH, Ko LW, Mattiace LA, Bucala R, Vlassara H: Glycation and microglial reaction in lesions of Alzheimer's disease. Neurobiol Aging. 1996, 17: 733-743.PubMed
  160. Ledesma MD, Bonay P, Colaco C, Avila J: Analysis of microtubule-associated protein tau glycation in paired helical filaments. J Biol Chem. 1994, 269: 21614-21619.PubMed
  161. Munch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Muller R, Neumann A, Schinzel R, Cunningham AM: Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Biochim Biophys Acta. 1997, 1360: 17-29.PubMed
  162. Lue LF, Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM, Stern DM, Yan SD: Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism. Exp Neurol. 2001, 171: 29-45.PubMed
  163. Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A, Yan SF, Stern A, et al: RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J. 2004, 23: 4096-4105.PubMed CentralPubMed
  164. Ko SY, Lin YP, Lin YS, Chang SS: Advanced glycation end products enhance amyloid precursor protein expression by inducing reactive oxygen species. Free Radic Biol Med. 2010, 49: 474-480.PubMed
  165. Cho HJ, Son SM, Jin SM, Hong HS, Shin DH, Kim SJ, Huh K, Mook-Jung I: RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer's disease animal model. FASEB J. 2009, 23: 2639-2649.PubMed
  166. Guglielmotto M, Aragno M, Tamagno E, Vercellinatto I, Visentin S, Medana C, Catalano MG, Smith MA, Perry G, Danni O, et al: AGEs/RAGE complex upregulates BACE1 via NF-kappaB pathway activation. Neurobiol Aging. 2012, 33: 196.e13-27.
  167. Jellinger KA, Paulus W, Wrocklage C, Litvan I: Effects of closed traumatic brain injury and genetic factors on the development of Alzheimer's disease. Eur J Neurol. 2001, 8: 707-710.PubMed
  168. Roberts GW, Gentleman SM, Lynch A, Graham DI: beta A4 amyloid protein deposition in brain after head trauma. Lancet. 1991, 338: 1422-1423.PubMed
  169. Uryu K, Laurer H, McIntosh T, Pratico D, Martinez D, Leight S, Lee VM, Trojanowski JQ: Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci. 2002, 22: 446-454.PubMed
  170. Blasko I, Beer R, Bigl M, Apelt J, Franz G, Rudzki D, Ransmayr G, Kampfl A, Schliebs R: Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer's disease beta-secretase (BACE-1). J Neural Transm. 2004, 111: 523-536.PubMed
  171. Chen XH, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Smith DH: Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol. 2004, 165: 357-371.PubMed CentralPubMed
  172. Loane DJ, Pocivavsek A, Moussa CE, Thompson R, Matsuoka Y, Faden AI, Rebeck GW, Burns MP: Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med. 2009, 15: 377-379.PubMed CentralPubMed
  173. Sanz O, Acarin L, Gonzalez B, Castellano B: NF-kappaB and IkappaBalpha expression following traumatic brain injury to the immature rat brain. J Neurosci Res. 2002, 67: 772-780.PubMed
  174. von Arnim CA, Tangredi MM, Peltan ID, Lee BM, Irizarry MC, Kinoshita A, Hyman BT: Demonstration of BACE (beta-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy. J Cell Sci. 2004, 117: 5437-5445.PubMed
  175. He X, Li F, Chang WP, Tang J: GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem. 2005, 280: 11696-11703.PubMed
  176. Wahle T, Prager K, Raffler N, Haass C, Famulok M, Walter J: GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network. Mol Cell Neurosci. 2005, 29: 453-461.PubMed
  177. Walker KR, Kang EL, Whalen MJ, Shen Y, Tesco G: Depletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1. J Neurosci. 2012, 32: 10423-10437.PubMed CentralPubMed
  178. Rocchi A, Orsucci D, Tognoni G, Ceravolo R, Siciliano G: The role of vascular factors in late-onset sporadic Alzheimer's disease. Genetic and molecular aspects. Curr Alzheimer Res. 2009, 6: 224-237.PubMed
  179. de la Torre JC: Pathophysiology of neuronal energy crisis in Alzheimer's disease. Neurodegener Dis. 2008, 5: 126-132.PubMed
  180. Koistinaho M, Koistinaho J: Interactions between Alzheimer's disease and cerebral ischemia–focus on inflammation. Brain Res Brain Res Rev. 2005, 48: 240-250.PubMed
  181. Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W: Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA. 2006, 103: 18727-18732.PubMed CentralPubMed
  182. Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S, Danni O, Parola M, Smith MA, 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.PubMed
  183. Bartus RT, Elliott PJ, Hayward NJ, Dean RL, Harbeson S, Straub JA, Li Z, Powers JC: Calpain as a novel target for treating acute neurodegenerative disorders. Neurol Res. 1995, 17: 249-258.PubMed
  184. Wang J, Liu S, Fu Y, Wang JH, Lu Y: Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat Neurosci. 2003, 6: 1039-1047.PubMed
  185. Wen Y, Yang SH, Liu R, Perez EJ, Brun-Zinkernagel AM, Koulen P, Simpkins JW: Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta. 2007, 1772: 473-483.PubMed
  186. Zhai DX, Kong QF, Xu WS, Bai SS, Peng HS, Zhao K, Li GZ, Wang DD, Sun B, Wang JH, et al: RAGE expression is up-regulated in human cerebral ischemia and pMCAO rats. Neurosci Lett. 2008, 445: 117-121.PubMed
  187. Pichiule P, Chavez JC, Schmidt AM, Vannucci SJ: Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia. J Biol Chem. 2007, 282: 36330-36340.PubMed
  188. Taylor CT: Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J Physiol. 2008, 586: 4055-4059.PubMed CentralPubMed
  189. Taylor CT, Cummins EP: The role of NF-kappaB in hypoxia-induced gene expression. Ann N Y Acad Sci. 2009, 1177: 178-184.PubMed
  190. O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B, Bembinster LA, Lammich S, et al: Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron. 2008, 60: 988-1009.PubMed CentralPubMed
  191. Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH, Zhong Z, Shen Y, et al: Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron. 2007, 54: 721-737.PubMed CentralPubMed
  192. Ohyagi Y, Asahara H, Chui DH, Tsuruta Y, Sakae N, Miyoshi K, Yamada T, Kikuchi H, Taniwaki T, Murai H, et al: Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease. FASEB J. 2005, 19: 255-257.PubMed
  193. Kitamura Y, Shimohama S, Kamoshima W, Matsuoka Y, Nomura Y, Taniguchi T: Changes of p53 in the brains of patients with Alzheimer's disease. Biochem Biophys Res Commun. 1997, 232: 418-421.PubMed
  194. Checler F, Sunyach C, Pardossi-Piquard R, Sevalle J, Vincent B, Kawarai T, Girardot N, St George-Hyslop P, da Costa CA: The gamma/epsilon-secretase-derived APP intracellular domain fragments regulate p53. Curr Alzheimer Res. 2007, 4: 423-426.PubMed
  195. Alves da Costa C, Paitel E, Mattson MP, Amson R, Telerman A, Ancolio K, Checler F: Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons. Proc Natl Acad Sci USA. 2002, 99: 4043-4048.PubMed CentralPubMed
  196. Alves da Costa C, Sunyach C, Pardossi-Piquard R, Sevalle J, Vincent B, Boyer N, Kawarai T, Girardot N, St George-Hyslop P, Checler F: Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease. J Neurosci. 2006, 26: 6377-6385.PubMed
  197. Dunys J, Sevalle J, Giaime E, Pardossi-Piquard R, Vitek MP, Renbaum P, Levy-Lahad E, Zhang YW, Xu H, Checler F, da Costa CA: p53-dependent control of transactivation of the Pen2 promoter by presenilins. J Cell Sci. 2009, 122: 4003-4008.PubMed CentralPubMed
  198. Checler F, Dunys J, Pardossi-Piquard R, Alves da Costa C: p53 is regulated by and regulates members of the gamma-secretase complex. Neurodegener Dis. 2010, 7: 50-55.PubMed
  199. Hunter S, Friedland RP, Brayne C: Time for a change in the research paradigm for Alzheimer's disease: the value of a chaotic matrix modeling approach. CNS Neurosci Ther. 2010, 16: 254-262.PubMed
  200. Ramsden M, Plant LD, Webster NJ, Vaughan PF, Henderson Z, Pearson HA: Differential effects of unaggregated and aggregated amyloid beta protein (1–40) on K(+) channel currents in primary cultures of rat cerebellar granule and cortical neurones. J Neurochem. 2001, 79: 699-712.PubMed
  201. Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA: The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J Neurosci. 2003, 23: 5531-5535.PubMed
  202. Giuffrida ML, Caraci F, Pignataro B, Cataldo S, De Bona P, Bruno V, Molinaro G, Pappalardo G, Messina A, Palmigiano A, et al: Beta-amyloid monomers are neuroprotective. J Neurosci. 2009, 29: 10582-10587.PubMed
  203. Baba A, Mitsumori K, Yamada MK, Nishiyama N, Matsuki N, Ikegaya Y: Beta-amyloid prevents excitotoxicity via recruitment of glial glutamate transporters. Naunyn Schmiedebergs Arch Pharmacol. 2003, 368: 234-238.PubMed
  204. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, et al: Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001, 60: 759-767.PubMed
  205. Zou K, Gong JS, Yanagisawa K, Michikawa M: A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci. 2002, 22: 4833-4841.PubMed
  206. Atwood CS, Obrenovich ME, Liu T, Chan H, Perry G, Smith MA, Martins RN: Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev. 2003, 43: 1-16.PubMed
  207. Lee HG, Casadesus G, Zhu X, Takeda A, Perry G, Smith MA: Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer disease. Ann N Y Acad Sci. 2004, 1019: 1-4.PubMed
  208. Armstrong RA: The pathogenesis of Alzheimer's disease: a reevaluation of the "amyloid cascade hypothesis". Int J Alzheimers Dis. 2011, 2011: 630865-PubMed CentralPubMed
  209. Chen Y, Huang X, Zhang YW, Rockenstein E, Bu G, Golde TE, Masliah E, Xu H: Alzheimer's beta-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of beta-Amyloid. J Neurosci. 2012, 32: 11390-11395.PubMed CentralPubMed
  210. Luo X, Yan R: Inhibition of BACE1 for therapeutic use in Alzheimer's disease. Int J Clin Exp Pathol. 2010, 3: 618-628.PubMed CentralPubMed
  211. Frautschy SA, Cole GM: Why pleiotropic interventions are needed for Alzheimer's disease. Mol Neurobiol. 2010, 41: 392-409.PubMed CentralPubMed
  212. Jaturapatporn D, Isaac MG, McCleery J, Tabet N: Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease. Cochrane Database Syst Rev. 2012, 2: CD006378-PubMed

Copyright

© Chami and Checler; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.