Abstract
Amyloid-β protein (Aβ) is the main component of neuritic plaques, the pathological hallmark of Alzheimer's disease (AD). β-site APP cleaving enzyme 1 (BACE1) is a major β-secretase contributing to Aβ generation. β-site APP cleaving enzyme 2 (BACE2), the homolog of BACE1, is not only a θ-secretase but also a conditional β-secretase. Previous studies showed that regulator of calcineurin 1 (RCAN1) is markedly increased by AD and promotes BACE1 expression. However, the role of RCAN1 in BACE2 regulation remains elusive. Here, we showed that RCAN1 increases BACE2 protein levels. Moreover, RCAN1 inhibits the turnover of BACE2 protein. Furthermore, RCAN1 attenuates proteasome-mediated BACE2 degradation, but not lysosome-mediated BACE2 degradation. Taken together, our work indicates that RCAN1 inhibits BACE2 turnover by attenuating proteasome-mediated BACE2 degradation. It advances our understanding of BACE2 regulation and provides a potential mechanism of BACE2 dysregulation in AD.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly
amyloid-β protein (Aβ) is derived from amyloid-β precursor protein (APP) by sequential cleavage of β- and γ-secretase [2,3,4]. β-site APP cleaving enzyme 1 (BACE1) is the major β-secretase contributing to Aβ generation [2]
Our work indicates that regulator of calcineurin 1 (RCAN1) inhibits BACE2 turnover by attenuating proteasome-mediated BACE2 degradation, leading to the upregulation of BACE2
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly. Neuritic plaques are the major pathological hallmark of AD, while amyloid-β protein (Aβ) is the main component of neuritic plaques [1]. Aβ is derived from amyloid-β precursor protein (APP) by sequential cleavage of β- and γ-secretase [2,3,4]. Β-site APP cleaving enzyme 1 (BACE1) is the major β-secretase contributing to Aβ generation [2]. Sun et al reported that β-site APP cleaving enzyme 2 (BACE2), the homolog of BACE1 cleaves APP at the Phe site to yield a C-terminal fragment (CTF) with 80 amino acids (CTFθ or C80), which is further cleaved by γ-secretase to release a truncated Aβ [3, 5, 6]. Overexpression of BACE2 in primary neurons derived from Swedish mutant APP transgenic mice significantly reduces Aβ generation [6]. BACE2 prevents neuronal apoptosis by cleaving a potassium channel at the surface of the neuronal plasma membrane [7]
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