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Keywords:

  • Alzheimer’s diseases;
  • BACE1;
  • gene expression;
  • transcription

Abstract

  1. Top of page
  2. Abstract
  3. BACE1 as the β-secretase in vivo
  4. BACE1 protein and its post-translational modifications
  5. Regulation of BACE1 gene expression
  6. The role of BACE1 gene expression regulation in Alzheimer’s disease
  7. Conclusion
  8. Acknowledgements
  9. Conflict of interests
  10. References

J. Neurochem. (2012) 120 (Suppl. 1), 62–70.

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaques are the hallmark neuropathology in AD brains. Proteolytic processing of amyloid-β precursor protein at the β site by beta-site amyloid-β precursor protein-cleaving enzyme 1 (BACE1) is essential to generate Aβ, a central component of the neuritic plaques. BACE1 is increased in some sporadic AD brains, and dysregulation of BACE1 gene expression plays an important role in AD pathogenesis. This review will focus on the regulation of BACE1 gene expression at the transcriptional, post-transcriptional, translation initiation, translational and post-translational levels, and its role in AD pathogenesis. Further studies on BACE1 gene expression regulation will greatly contribute to our understanding of AD pathogenesis and reveal potential novel approaches for AD prevention and drug development.


Abbreviations used

amyloid β protein

AD

Alzheimer’s disease

ADAM

A Disintegrin And Metalloprotease domain

APP

amyloid β precursor protein

BACE1

beta-site APP-cleaving enzyme 1

cdk5

cyclin-dependent kinase 5

ER

endoplasmic reticulum

HIF1

hypoxia-inducible factor 1

IκB

inhibitor of κB

NSAID

non-steroidal anti-inflammatory drug

PPARγ

peroxisome proliferator-activated receptor-gamma

STAT

signal transducer and activator of transcription

UTR

5′ untranslated region

BACE1 as the β-secretase in vivo

  1. Top of page
  2. Abstract
  3. BACE1 as the β-secretase in vivo
  4. BACE1 protein and its post-translational modifications
  5. Regulation of BACE1 gene expression
  6. The role of BACE1 gene expression regulation in Alzheimer’s disease
  7. Conclusion
  8. Acknowledgements
  9. Conflict of interests
  10. References

In 1906, Dr Alois Alzheimer described neuropathological changes, including neuritic plaques and neurofibrillary tangles, in the brains of an individual with a subtype of dementia. The disorder with such pathology was later named Alzheimer’s disease (AD) in recognition of his contribution. Almost a century later, Glenner and Wong (1984a,b) isolated a small peptide termed amyloid β protein (Aβ) from neuritic plaques-enriched AD brains (Glenner and Wong (1984a,b)), and several years later, the amyloid-β precursor protein (APP) gene was identified by several groups (Goldgaber et al. 1987; Kang et al. 1987; Robakis et al. 1987; Tanzi et al. 1987). Aβ is generated from APP through sequential cleavages by β-secretase and γ-secretase (Li et al. 2006). Subsequently, a large effort has been directed to identifying the proteases and defining the mechanism underlying these cleavages.

Using a variety of techniques, including expression cloning, genomic searches, and protein purification, beta-site APP-cleaving enzyme 1 (BACE1) was identified as the β-secretase (Hussain et al. 1999; Sinha et al. 1999; Vassar et al. 1999; Yan et al. 1999). BACE1 matches the tissue distribution, subcellular localization, optimum pH and substrate sequence preference of β-secretase in vivo. Cleavage of APP at two sites by BACE1 produces a secreted form of APP and a 99 or 89-residue membrane-associated C-terminal fragment (C99, or C89 respectively). C99 is subsequently cleaved by γ-secretase at intramembrane sites to generate Aβ and c-terminal fragment-γ fragments in the amyloidogenic pathway, whereas, in a non-amyloidogenic pathway, cleavage of APP first within the Aβ domain by α-secretase, possibly involving A Disintegrin And Metalloprotease domain 9 (ADAM9), ADAM10, and ADAM17/ Tissue necrosis factor-alpha converting enzyme, generates a secreted form of APP and C83. C83 is subsequently cleaved by γ-secretase, precluding Aβ generation. The non-amyloidogenic pathway is the dominant pathway in vivo under normal conditions (Fig. 1).

image

Figure 1.  Generation of Aβ from APP by cleavage of β and γ-secretase. APP is a type I membrane protein. APP is processed by α, β and γ-secretase. The non-amyloidogenic pathway is the predominant pathway for processing of APP under normal conditions in which APP is cleaved by α and γ-secretase. In the amyloidogenic pathway, APP is cleaved by β-secretase to produce C99, which is subsequently cleaved by γ-secretase to generate Aβ.

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Elevated BACE1 gene expression was found in sporadic cases of AD by several groups (Fukumoto et al. 2002; Holsinger et al. 2002; Yang et al. 2003; Li et al. 2004; Chen et al. 2011). This suggests that the regulation of BACE1 expression plays an important role in AD pathogenesis. This review will focus on the regulation of BACE1 gene expression, particularly at transcriptional and post-transcriptional levels, and its role in AD pathogenesis.

BACE1 protein and its post-translational modifications

  1. Top of page
  2. Abstract
  3. BACE1 as the β-secretase in vivo
  4. BACE1 protein and its post-translational modifications
  5. Regulation of BACE1 gene expression
  6. The role of BACE1 gene expression regulation in Alzheimer’s disease
  7. Conclusion
  8. Acknowledgements
  9. Conflict of interests
  10. References

β-Secretase is a member of the aspartyl protease family, and the family itself belongs to a larger group of endopeptidases whose catalytic activity is dependent on aspartate residues. BACE1 is a type I membrane-bound aspartyl protease of 501 amino acids. The human BACE1 gene is located on chromosome 11 and contains nine exons and eight introns, spanning a 30.6 kb region from 11q23.2 to 11q23.3. BACE1 pre-mRNA undergoes complex alternative splicing, resulting in various protein isoforms that differ in enzymatic activities. In addition to a full-length BACE1 of 501 amino acids, there are splicing variants of 476, 457, and 432 amino acids (Bodendorf et al. 2001; Murphy et al. 2001; Tanahashi and Tabira 2001; Ehehalt et al. 2002; Zohar et al. 2003). A sequence from exon 3 to exon 5 was found to be essential in correct splicing (Mowrer and Wolfe 2009). Alternative splicing could contribute to the differential activity of BACE1 in brain and pancreas (Mowrer and Wolfe 2008). Full-length BACE1-501 is endoglycosylase-H resistant, while BACE1-457 and BACE1-476 are sensitive to endoglycosylase-H treatment, suggesting these forms are localized to the endoplasmic reticulum (ER) (Tanahashi and Tabira 2001); however, only a small amount of BACE1 could be observed in the ER and lysosome, with the majority being located in endosomes and the Golgi (Vassar et al. 1999). Compared with BACE1-501, BACE1-457 and BACE1-476 have reduced β-secretase activity (Bodendorf et al. 2001; Tanahashi and Tabira 2001; Ehehalt et al. 2002).

BACE1 belongs to the pepsin family, which includes cathepsin D, cathepsin E, chymosin, gastricsin, pepsin A, pepsin F, renin, and BACE2, a homolog of BACE1 with distinct transcriptional regulation and function (Sun et al. 2005, 2006b). Although this family of proteins display sequence homology, their substrate preference and inhibitor profiles share little similarity (Gruninger-Leitch et al. 2002). Aspartyl proteases are bi-lobed proteins with an aspartate residue motif D(T/S)G in each lobe (Dunn 2002). BACE1 has two DTGS and DSGT motifs at 93 and 289. These aspartate residues are conserved (Hong et al. 2000), and mutation of either obliterates enzyme activity (Hussain et al. 1999; Bennett et al. 2000).

BACE1 undergoes a complex set of post-translational modifications during its maturation. It is synthesized as a precursor protein containing a 21 amino acid signal peptide followed by an N-terminal pro-peptide domain that is removed at residue E46 by furin or furin-like convertases in the trans-Golgi network (Bennett et al. 2000; Capell et al. 2000; Benjannet et al. 2001; Creemers et al. 2001). The pro-peptide is required for the protein to efficiently exit the ER but will not inhibit β-site cleavage, as pro-BACE retains β-secretase activity (Benjannet et al. 2001); however, this pro-peptide is important in facilitating correct folding of the protease domain (Shi et al. 2001). Prior to pro-peptide cleavage and subsequent maturation, BACE1 is processed between Leu228 and Ala229 to generate stable N-and C-terminal fragments which remain covalently associated via a disulfide bond (Huse et al. 2003). This dimerization may facilitate binding and cleavage of BACE1 substrates (Schmechel et al. 2004; Westmeyer et al. 2004).

The β-secretase activity of BACE1 is dependent on the extent of N-glycosylation at Asn -153, -172, -223 and -354 (Capell et al. 2000; Haniu et al. 2000; Huse and Doms 2000; Charlwood et al. 2001), and mature N-glycosylated moieties can be sulfated (Benjannet et al. 2001). While two O-glycosylation sites at T80 and T155 were predicted by the NetOGlyc 3.1 program (unpublished data from our laboratory), it is still unknown what effects these changes would have on BACE1 function.

BACE1 contains six Cys residues which form three disulfide bridges connecting C216 to C420, C278 to C443, and C330 to C380 (Haniu et al. 2000; Fischer et al. 2002). While critical for BACE1 maturation, they are not essential for APP processing (Fischer et al. 2002). Three other Cys residues, C478, C482, and C485, are palmitoylated within the transmembrane/cytosolic tail region which suppresses BACE1 shedding but has little effect on β-secretase activity (Benjannet et al. 2001).

Phosphorylation of the cytoplasmic domain plays an important role in both BACE1 maturation and intracellular trafficking through the trans-Golgi network and endosomal system (Capell et al. 2000; Haniu et al. 2000; Walter et al. 2001). When fully matured, BACE1 is phosphorylated at S498 by casein kinase 1 (CK-1) (Walter et al. 2001). A study by Qing et al. (2004) showed that BACE1 is ubiquitinated and degraded via the ubiquitin-proteasome pathway, and pulse-chase experiments demonstrated that BACE1 has a half-life of 9 h. Inhibiting the ubiquitin-proteasome pathway by specific proteasome inhibitors markedly enhanced the generation of C99 and Aβ, further supporting this route of degradation (Qing et al. 2004).

In addition to the degradation of BACE1 by the ubiquitin-proteasome pathway, BACE1 can also be degraded by the lysosomal pathway (Koh et al. 2005). Cerebral ischemia resulted in caspases activation, which induced BACE1 stability and enzymatic activity. The underlying mechanism involved caspase-dependent cleavage of GGA3, an adaptor protein involved in BACE1 trafficking and lysosomal degradation (Tesco et al. 2007). Levels of GGA3 were found to be decreased in AD brain samples, which correlated with increased expression of BACE1 (Tesco et al. 2007).

Regulation of BACE1 gene expression

  1. Top of page
  2. Abstract
  3. BACE1 as the β-secretase in vivo
  4. BACE1 protein and its post-translational modifications
  5. Regulation of BACE1 gene expression
  6. The role of BACE1 gene expression regulation in Alzheimer’s disease
  7. Conclusion
  8. Acknowledgements
  9. Conflict of interests
  10. References

BACE1 has a tissue-specific expression pattern. Although BACE1 is expressed in all tissues, BACE1 mRNA is expressed most highly in the pancreas and also at high levels in the brain, where all four isoforms are expressed (Yan et al. 1999; Ehehalt et al. 2002). BACE1 could be detected in neurons in all brain regions, but could not be detected in glial cells (Yan et al. 1999; Vassar et al. 1999; Marcinkiewicz and Seidah 2000).

The BACE1 gene expression is tightly regulated at the transcriptional level. The promoter of human BACE1 gene was firstly cloned and characterized by Dr Song’s laboratory in 2004 (Christensen et al. 2004), and by Dr Lahiri’s group in the same year (Ge et al. 2004; Sambamurti et al. 2004). The human BACE1 gene has a complex regulatory unit and its promoter contains many putative transcription factor-binding sites, such as a GC box, HSF-1, PU-box, AP1, and lymphokine response element (Christensen et al. 2004). The BACE1 promoter also contains an AP2 site (Ge et al. 2004). Transcription factor Sp1 plays a significant role in regulating BACE1 gene expression and such regulation affects β-secretase processing of APP and Aβ production (Christensen et al. 2004). In rat neurons and astrocytes, the transcription factor Yin Yang 1 can activate BACE1 gene expression through a putative responsive element within the BACE1 promoter (Nowak et al. 2006). Constitutive Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT)1 signaling contributed to the basal expression of BACE1 and subsequent Aβ generation in neurons (Cho et al. 2009), and an increase in intracellular calcium concentration, induced by Aβ or a calcium ionophore could also stimulate BACE1 gene expression through calcineurin-nuclear factor of activated T-cells (NFAT) signaling (Cho et al. 2008). Further studies demonstrated that the BACE1 gene promoter also contains functional cis-acting binding elements for nuclear factor-kappa B (NF-κB) p65 and the peroxisome proliferator-activated receptor-gamma (PPARγ) (Sastre et al. 2006; Bourne et al. 2007; Chen et al. 2011), and the BACE1 gene is transcriptionally regulated by NF-κB and PPARγ signaling pathways (Sastre et al. 2006; Buggia-Prevot et al. 2008; Chen et al. 2011).

APP undergoes amyloidogenic and non-amyloidogenic pathways. The amyloidogenic pathway via β-secretase and γ-secretase accounts for the minority of APP processing, resulting in a very small amount of Aβ generation in normal brains. Under normal conditions the non-amyloidogenic pathway via α-secretase is predominant. Tightly controlled BACE1 gene expression plays an essential role in regulating APP processing pathways. Although the APP gene is robustly expressed in neuronal and non-neuronal cells under a strong housekeeping gene-like promoter (Song and Lahiri 1998a; b), the expression of the human BACE1 gene is relatively low under normal conditions because of a very weak promoter (Li et al. 2006). Li et al. (2006) reported that human BACE1 gene transcription is much lower than APP gene transcription, and that BACE1 mRNA levels were markedly lower than APP mRNA levels in both neuronal and non-neuronal cells. Promoter assays showed that human BACE1 promoter activity is significantly weaker than human APP promoter activity. This indicates that lower BACE1 gene expression resulted from a weaker BACE1 gene promoter (Li et al. 2006). Furthermore, at the translation initiation level, phosphorylation of translation initiation factor eIF2alpha increased BACE1 protein expression and amyloidogenesis (O’Connor et al. 2008), and the AUGs in the 5′ untranslated region (UTR) of BACE1 gene regulate BACE1 expression by suppressing initiation of translation (Lammich et al. 2004; Rogers et al. 2004). There are six upstream ATGs and the corresponding upstream open reading frames between the transcription initiation site and the physiological translation initiation codon of the human BACE1 gene (Zhou and Song 2006). The fourth uAUG in the 5′UTR of the human BACE1 mRNA can function efficiently as a translation initiation site and the fourth upstream open reading frame further contributes to the weak translation of BACE1. Leaky scanning and reinitiation are involved in inhibition of the physiological AUG-initiated BACE1 translation. Such leaky scanning and reinitiation result in weak translation of BACE1 under normal conditions (Zhou and Song 2006). Taken together, the weak promoter and further controlled initiation by the 5′UTR results in limited BACE1 transcription and a very low level of BACE1 translation under normal conditions. Despite robust APP expression, low levels of BACE1 protein because of limited BACE gene expression is responsible for the minority of APP undergoing the amyloidogenic pathway and relatively lower levels of Aβ production under normal conditions (Li et al. 2006; Zhou and Song 2006).

The role of BACE1 gene expression regulation in Alzheimer’s disease

  1. Top of page
  2. Abstract
  3. BACE1 as the β-secretase in vivo
  4. BACE1 protein and its post-translational modifications
  5. Regulation of BACE1 gene expression
  6. The role of BACE1 gene expression regulation in Alzheimer’s disease
  7. Conclusion
  8. Acknowledgements
  9. Conflict of interests
  10. References

AD pathogenesis is believed to be multifactorial and the underlying mechanism remains elusive. Abnormal gene regulation could be one of the factors associated with abnormal processing of APP and increased Aβ levels in AD. Recent studies show that transcriptional dysregulation of human BACE1 gene expression contributes to AD pathogenesis (citation) Although genetic analysis has failed to uncover any BACE1 coding mutation in patients with familial AD (Cruts et al. 2001; Nicolaou et al. 2001; Zhou et al. 2010), increased β-secretase activity was reported in some familial AD brains (Russo et al. 2000) and greater expression levels of BACE1 was found in the cortex of sporadic AD patients versus controls (Holsinger et al. 2002; Fukumoto et al. 2002, 2004; Yang et al. 2003; Chen et al. 2011). BACE1 levels were also significantly increased in Down Syndrome brain tissues, which resulted in markedly increased Aβ production in the AD pathogenesis of Down Syndrome (Sun et al. 2006c). Although in transgenic mice there is no significant change in BACE1 mRNA levels, BACE1 levels were elevated in neurons around amyloid plaques (Zhao et al. 2007). Tissue-specific expression of BACE1 is very important for APP processing and Aβ production and a slight increase of BACE1 expression could induce a dramatic elevation in Aβ production, facilitating plaque formation under pathological conditions (Li et al. 2006). Thus, dysregulation of BACE1 gene expression at the transcription and translation level could play an important role in AD pathogenesis.

A majority of AD cases are sporadic with late onset and no defined cause. A history of stroke increases AD prevalence by two fold (Snowdon et al. 1997; White et al. 2002; Schneider et al. 2003; Vermeer et al. 2003; Altieri et al. 2004). Hypoxia is a direct consequence of hypoperfusion, a common cerebral vascular component among AD risk factors, and it may play an important role in AD pathogenesis. Hypoxia-inducible factor 1 (HIF1) is the principal molecule regulating oxygen homeostasis (Huang et al. 1999). HIF1 is a member of the basic helix-loop-helix transcription factor family, and the basic region of the protein binds specifically to the 5′-RCGTG hypoxia response element in a gene promoter. HIF1 contains an oxygen-regulated expression subunit α (HIF1α) and a constitutively expressed subunit β (HIF1β) (ARNT). HIF1α, mediated by its oxygen-dependent degradation domain, is rapidly degraded through the ubiquitin proteasome pathway under normoxic conditions with a half-life of less than five minutes, while it is stabilized under hypoxic conditions (Huang and Bunn 2003). HIF1 is up-regulated in the human frontal cortex with aging (Lu et al. 2004). Sun et al. (2006a) discovered that the human BACE1 gene contains a functional hypoxia response element in its promoter and hypoxia up-regulated β-secretase cleavage of APP and Aβ production by increasing BACE1 gene transcription and expression both in vitro and in vivo. This finding was supported by studies using SH-SY5Y and N2a cells (Xue et al. 2006), and conditional HIF1α-KO mice (Zhang et al. 2007). Furthermore, hypoxia treatment markedly increased Aβ deposition and neuritic plaque formation as well as potentiated the memory deficit in Swedish mutant APP transgenic mice (Sun et al. 2006a). These studies clearly demonstrate that hypoxia can facilitate AD pathogenesis via activating BACE1 gene expression and provide a novel molecular mechanism to link vascular factors to AD (Fig. 2). Cerebral vascular abnormalities could also affect BACE1 at a post-translational level. A report showed that depletion of GGA3 (Golgi-localized γ-ear-containing ARF-binding protein) increases BACE1 and enhances β-secretase activity because of post-translational stabilization following caspase activation during cerebral ischemia. GGA3 protein levels were significantly decreased and inversely correlated with increased levels of BACE1 in AD brain samples (Tesco et al. 2007).

image

Figure 2.  Up-regulation of BACE1 by hypoxia facilitates AD pathogenesis. Risk factors of AD, such as stroke, aging and atherosclerosis, result in brain hypoperfusion and hypoxia. Transcription factor HIF1 is induced under hypoxia conditions and activates the BACE1 gene promoter through a hypoxia responsive element within the promoter. Transcriptional activation of the BACE1 gene results in increased BACE1 protein levels and enzymatic activity, in turn potentiating APP processing at the β-site to generate more Aβ. Accumulation and deposition of Aβ in the brain subsequently leads to memory deficits and AD pathogenesis.

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Inflammation is one of the major pathological changes in AD brains and NF-κB signaling plays an important role in inflammation and oxidative stress (Tong et al. 2005). Oxidative stress has long been implicated in AD pathogenesis. The levels of several molecular species representing in vivo oxidative stress were elevated in AD brains (Smith et al. 1997; Sayre et al. 1997; Montine et al. 1998; Nourooz-Zadeh et al. 1999; Nunomura et al. 1999). H2O2 can up-regulate BACE1 gene transcription, resulting in more C99 production and Aβ generation (Tong et al. 2005). NF-κB activation was implicated in H2O2-induced oxidative stress and NF-κB activity was increased in AD brains (Schreck et al. 1991; Kaltschmidt et al. 1997; Chen et al. 2011). In the NF-κB signaling pathway, binding of inhibitor of κB (IκB) to NF-κB dimers, mostly RelA (p65)/p50, causes the dimers to be sequestered in the cytoplasm and remain inactive. When NF-κB-activating stimuli activate the IκB Kinase complex, IκB Kinase phosphorylates IκB, and NF-κB is released to the nucleus, where p65/p50 dimers bind to 5′-GGGRNNYYCC NF-κB binding elements in the promoter of target genes to modulate gene expression (Miyamoto and Verma 1995; Baldwin 1996). It was reported that a rat BACE1 promoter contains a NF-κB binding element (Bourne et al. 2007), and using the same rat promoter, exacerbated Aβ levels were shown to modulate rat BACE1 promoter activity via a NF-κB-dependent pathway (Buggia-Prevot et al. 2008). A recent report from our study showed that both BACE1 and NF-κB p65 levels were significantly increased in the brains of AD patients. Two functional NF-κB binding elements were identified in the human BACE1 promoter region (Chen et al. 2011). Expression of NF-κB p65 resulted in increased BACE1 promoter activity and BACE1 transcription, while disruption of NF-κB p65 decreased BACE1 gene expression in p65-knockout cells. In addition, NF-κB p65 expression leads to up-regulated β-secretase cleavage and Aβ production. The results clearly demonstrate that NF-κB binding elements on the BACE1 promoter are able to regulate BACE1 gene transcription, and activation of the NF-κB signaling pathway can facilitate BACE1 gene expression and APP processing to generate more Aβ. This could form a vicious loop that exuberated oxidative stress and inflammatory responses induced by abnormal Aβ aggregation and plaque formation result in activation of NF-κB signaling, in turn triggering more Aβ production by up-regulating BACE1 gene expression. Increased BACE1 expression and APP processing mediated by NF-κB signaling in brain could be one of the novel molecular mechanisms underlying the development of AD in some sporadic cases. Furthermore, a p25/ cyclin-dependent kinase 5 (cdk5) responsive region containing multiple sites for STAT1/3 was identified in the BACE1 promoter (Wen et al. 2008). cdk5 has been implicated in AD pathogenesis, and cdk5/p25 signaling has been shown to increase Aβ generation through STAT-3-mediated transcriptional control of BACE1 gene expression. This study provided additional evidence that transcriptional dysregulation of BACE1 gene expression contributes to the development of Alzheimer’s disease.

BACE1 gene expression is also regulated at the post-transcription level by microRNAs (miRNAs). miRNAs are small post-transcriptional regulatory RNAs. By using miRNA expression microarray, decreased miR-107 level was identified in brain samples from AD patients (Wang et al. 2008; Nelson and Wang 2010). BACE1 mRNA levels tended to increase as miR-107 levels decreased in the progression of AD. A miR-107 miRNA recognition sequence was identified from the 3′UTR of BACE1 mRNA and could be responsible for the increased BACE1 levels in AD brains (Wang et al. 2008). Another miRNA profiling study in sporadic AD cases identified that miR-29a/b-1 was significantly decreased in AD patients that had abnormally high levels of BACE1 protein expression (Hebert et al. 2008). miR-29a/b-1 regulated Aβ production and BACE1 expression through its recognition motif within the 3′UTR of BACE1 (Hebert et al. 2008). A BACE1 antisense transcript (BACE1-AS) was also identified through the functional annotation of the mammalian genome large-scale transciptome study and was shown to regulate BACE1 expression in vitro and in vivo. BACE1-AS levels were levated in AD patients and AD model mice (Faghihi et al. 2008). Furthermore, various stressors including Aβ42 could activate BACE1-AS and stabilize BACE1 mRNA, generating additional Aβ through a feed-forward mechanism (Faghihi et al. 2008).

BACE1 has been considered as one of the major targets for AD drug development, as it is essential for APP processing, and regulation of BACE1 gene expression is critical for controlling Aβ production. Targeting and modulating BACE1 gene expression regulation could be a valuable avenue for an anti-Aβ strategy of treating AD (Li et al. 2006; Zhou and Song 2006). It has been shown that the BACE1 gene is transcriptionally regulated by NF-κB and PPARγ signaling pathways (Sastre et al. 2006; Buggia-Prevot et al. 2008; Chen et al. 2011). Some non-steroidal anti-inflammatory drugs (NSAIDs) have been demonstrated to have therapeutic potential in AD treatment by altering amyloidogenic APP processing and reducing Aβ generation (Blasko et al. 2001; Weggen et al. 2001; Sastre et al. 2006). One of the mechanisms underlying the protective effects of NSAIDs in AD involves activation of PPARγ and decreased BACE1 gene transcription (Sastre et al. 2006). Furthermore, NSAIDs were shown to inhibit BACE1 transcriptional activation induced by the strong NF-κB activator – tumor necrosis factor-alpha (TNFα), and block inflammation-induced BACE1 transcription and Aβ production (Chen et al. 2011). Because of the vital role of BACE1 in Aβ generation in the pathological progression of AD (Li et al. 2006), these studies suggest that transcriptional inhibition of BACE1 gene expression may be a valuable drug target for AD therapy.

Conclusion

  1. Top of page
  2. Abstract
  3. BACE1 as the β-secretase in vivo
  4. BACE1 protein and its post-translational modifications
  5. Regulation of BACE1 gene expression
  6. The role of BACE1 gene expression regulation in Alzheimer’s disease
  7. Conclusion
  8. Acknowledgements
  9. Conflict of interests
  10. References

Proteolytic processing of APP at the β-site by BACE1 is essential to generate Aβ, a central component of neuritic plaques in AD brains. It has been shown that BACE1 is increased in some sporadic AD brains. BACE1 gene expression is tightly controlled, and dysregulation of BACE1 expression at transcriptional, post-transcriptional, translation initiation, translational or post-translational levels may play an important role in AD pathogenesis (Fig. 3). Further studies on BACE1 gene expression regulation will greatly contribute to our understanding of AD pathogenesis and reveal novel approaches which could be potentially effective for AD prevention and drug development.

image

Figure 3.  Tight regulation of BACE1 from transcriptional, post-transcriptional as well as post-translational levels. Various transcription factors have been identified to regulate BACE1 gene promoter activity at the transcriptional level. Furthermore, BACE1 mRNA is regulated at the post-transcriptional level by the uAUGs of the 5′UTR, alternative splicing, and miRNAs at the 3′UTR. BACE1 proteins also undergoes a series of post-translational modifications which affect its maturation, trafficking, stability, and enzymatic activity. TSS, the transcription start site.

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Acknowledgements

  1. Top of page
  2. Abstract
  3. BACE1 as the β-secretase in vivo
  4. BACE1 protein and its post-translational modifications
  5. Regulation of BACE1 gene expression
  6. The role of BACE1 gene expression regulation in Alzheimer’s disease
  7. Conclusion
  8. Acknowledgements
  9. Conflict of interests
  10. References

This work was supported by the Canadian Institutes of Health Research (CIHR) Operating Grant MOP-97825. WS is the holder of the Canada Research Chair in Alzheimer’s disease.

References

  1. Top of page
  2. Abstract
  3. BACE1 as the β-secretase in vivo
  4. BACE1 protein and its post-translational modifications
  5. Regulation of BACE1 gene expression
  6. The role of BACE1 gene expression regulation in Alzheimer’s disease
  7. Conclusion
  8. Acknowledgements
  9. Conflict of interests
  10. References