BACE1 is the major β-secretase for generation of Aβ peptides by neurons

Cai, Huaibin; Wang, Yanshu; McCarthy, Diane; Wen, Hongjin; Borchelt, David R.; Price, Donald L.; Wong, Philip C.

doi:10.1038/85064

Cited by 1,009 publications

(780 citation statements)

References 13 publications

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“…As the only β-secretase known to generate Aβ in brain, BACE has proven to be a key molecule in the formation of senile plaques [8,9,43,44]. Up to now, studies of BACE have concentrated on its structure [4,45], trafficking [11,16,[46][47][48][49][50], and specific inhibition [10], but how its activity is regulated remains largely unclear.…”

Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

et al. 2007

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Amyloid-β (Aβ) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated by β-secretase-and γ-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP). The aspartic protease, β -site APP cleavage enzyme (BACE), has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases (RTKs), such as the receptors for epidermal growth factor (EGF) and nerve growth factor (NGF), in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and Aβ production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.

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Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

et al. 2007

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“…Mice-BACE1 Ϫ/Ϫ mice were purchased from The Jackson Laboratory (Bar Harbor, ME) (15). BACE1 ϩ/Ϫ mice were used for breeding, and all wild-type controls used were BACE1 ϩ/ϩ littermates.…”

Section: Methodsmentioning

confidence: 99%

“…To determine whether therapeutic BACE1 inhibition would cause mechanism-based toxicity, several lines of BACE1 null mice were generated by gene targeting (13)(14)(15). Initial reports indicated that BACE1 Ϫ/Ϫ mice were viable, fertile, and devoid of abnormalities.…”

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confidence: 99%

β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects

Hitt¹,

Riordan²,

Kukreja

et al. 2012

Journal of Biological Chemistry

140

151

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Background:Little is known about BACE1 functions. Results: BACE1 Ϫ/Ϫ mice have axon guidance defects similar to those of CHL1 Ϫ/Ϫ mice; CHL1 undergoes BACE1-dependent processing in vivo; CHL1 and BACE1 co-localize in terminals and growth cones. Conclusion: BACE1 deficiency produces a CHL1 loss-of-function phenotype. Significance: BACE1 inhibition may cause axon guidance defects, adding a note of caution to BACE1 inhibitor drug development.

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“…BACE1 deficiency abolishes Ab production in BACE1 knockout mouse (Cai et al, 2001;Luo et al, 2001;Roberds et al, 2001) and in cell cultures (Cai et al, 2001;Roberds et al, 2001). BACE mRNA and protein levels and b-secretase activities were reported to be induced by a combination of proinflammatory cytokines and suppressed by NSAIDs and peroxisome proliferator-activated receptor gamma (PPARg) agonist in vitro (Sastre et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Morita

Teter

Yang

et al. 2005

Neuropsychopharmacol

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Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Ab) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Ab production has not been ruled out. We show that ibuprofen reduced Ab brain levels in rats from exogenously infused Ab in the absence of altered Ab production. To determine whether ibuprofen inhibits proamyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Ab and inflammation-related molecules a 1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor g) (PPARg) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1b, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Ab42 production, these observations suggest that ibuprofen reduction of Ab pathology may not be mediated by altered Ab42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1b and its downstream target ACT).

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BACE1 is the major β-secretase for generation of Aβ peptides by neurons

Cited by 1,009 publications

References 13 publications

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

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