Abstract
BackgroundAlzheimer’s disease is the most common neurodegenerative disease in the elderly. Amyloid-β protein (Aβ) is the major component of neuritic plaques which are the hallmark of AD pathology. β-site APP cleaving enzyme 1 (BACE1) is the major β-secretase contributing to Aβ generation. β-site APP-cleaving enzyme 2 (BACE2), the homolog of BACE1, might play a complex role in the pathogenesis of Alzheimer’s disease as it is not only a θ-secretase but also a conditional β-secretase. Dysregulation of BACE2 is observed in Alzheimer’s disease. However, the regulation of BACE2 is less studied compared with BACE1, including its degradation pathways. In this study, we investigated the turnover rates and degradation pathways of BACE2 in both neuronal cells and non-neuronal cells.ResultsBoth lysosomal inhibition and proteasomal inhibition cause a time- and dose-dependent increase of transiently overexpressed BACE2 in HEK293 cells. The half-life of transiently overexpressed BACE2 protein is approximately 6 h. Moreover, the half-life of endogenous BACE2 protein is approximately 4 h in both HEK293 cells and mouse primary cortical neurons. Furthermore, both lysosomal inhibition and proteasomal inhibition markedly increases endogenous BACE2 in HEK293 cells and mouse primary cortical neurons.ConclusionsThis study demonstrates that BACE2 is degraded by both the proteasome and lysosome pathways in both neuronal and non-neuronal cells at endogenous level and in transient overexpression system. It indicates that BACE2 dysregulation might be mediated by the proteasomal and lysosomal impairment in Alzheimer’s disease. This study advances our understanding of the regulation of BACE2 and provides a potential mechanism of its dysregulation in Alzheimer’s disease.
Highlights
Alzheimer’s disease is the most common neurodegenerative disease in the elderly
Deposition of Amyloid-β protein (Aβ) is formed from amyloid-β precursor protein (APP) by sequential cleavage of β- and γ-secretase [2].β-site APP cleaving enzyme 1 (BACE1) is the major β-secretase contributing to Aβ generation.β-site APP-cleaving enzyme 2 (BACE2), the homolog of BACE1, is a θ-secretase, which cleaves APP at Phe20 site to yield a CTF with 80 amino acids (CTFθ or C80) contributing to the generation of a truncated Aβ [3, 4]
Our recent study demonstrated that β-site APP cleaving enzyme 2 (BACE2) can be converted into a β-secretase with comparable β-secretase activity to that of BACE1, implying that BACE2 could contribute to Aβ generation in Alzheimer’s disease (AD) [6].Consistently, increased BACE2 expression and activity is detected in neurons of AD brains [7]
Summary
Alzheimer’s disease is the most common neurodegenerative disease in the elderly. Amyloid-β protein (Aβ) is the major component of neuritic plaques which are the hallmark of AD pathology. β-site APP cleaving enzyme 1 (BACE1) is the major β-secretase contributing to Aβ generation. β-site APP-cleaving enzyme 2 (BACE2), the homolog of BACE1, might play a complex role in the pathogenesis of Alzheimer’s disease as it is a θsecretase and a conditional β-secretase. Β-site APP cleaving enzyme 1 (BACE1) is the major β-secretase contributing to Aβ generation. Β-site APP-cleaving enzyme 2 (BACE2), the homolog of BACE1, might play a complex role in the pathogenesis of Alzheimer’s disease as it is a θsecretase and a conditional β-secretase. The association between a number of SNPs in BACE2 and AD was detected in APOE ε4 non-carriers, which might be mediated by altered BACE2 expression-mediated Aβ generation and clearance [10]. It indicates that dysregulation of BACE2 might contribute to the pathogenesis AD
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