BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis

Wang, Zhe; Xu, Qin; Cai, Fei; Liu, Xi; Wu, Yili; Song, Weihong

doi:10.1172/jci.insight.123431

Cited by 59 publications

(48 citation statements)

References 59 publications

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“…Moreover, BACE2 prevents neuronal apoptosis by cleaving a potassium channel at the surface of plasma membrane [5]. However, our recent study demonstrated that 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 AD [6].Consistently, increased BACE2 expression and activity is detected in neurons of AD brains [7]. Genetic data highly supports that BACE2 is associated with AD risk.…”

Section: Introductionsupporting

confidence: 56%

“…C57BL/6 mice were obtained from Cyagen Bioscience. Mouse cortical neurons were prepared from E18 embryos as described previously [6]. Briefly, the cortices of embryos were dissected out and the meninges were completely removed.…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…Then, the papain solution was replaced with inactivation solution (MEM containing 0.6% D-[+]-glucose, 1 mM pyruvate, 10% horse serum, 2.5% bovine serum albumin [BSA], and 2.5% trypsin inhibitor) and the cells were dissociated by repeatedly pipetting. The isolated cells were equally seeded on poly-D-lysine-coated dishes with Neurobasal Media (Invitrogen) containing B27 [6]. All cells were maintained at 37°C with 5% CO 2 in an incubator as described previously [16,18,21].…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

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BACE2 degradation is mediated by both the proteasome and lysosome pathways

Qiu

Liang

Wang

et al. 2020

BMC Mol and Cell Biol

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Background: 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 not only a θsecretase 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. Results: Both 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. Conclusions: This 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.

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Section: Introductionsupporting

confidence: 56%

Section: Cell Culture and Transfectionmentioning

confidence: 99%

Section: Cell Culture and Transfectionmentioning

confidence: 99%

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BACE2 degradation is mediated by both the proteasome and lysosome pathways

Qiu

Liang

Wang

et al. 2020

BMC Mol and Cell Biol

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“…Although analysis of BACE2 expression in human and rat tissues revealed that most of the brain regions expressed low level of Bace2 mRNA [40], a recent study indicated that BACE2 is present in a specific subsets of the neurons and glial cells of the mouse brain [41]. Furthermore, BACE2 expression was reported to increase in the brains of aged vs young mice [42]. Hence, BACE2 may be physiologically relevant protease responsible for liberation of NRG2 ectodomain in the adult brain, where NRG2 is primarily expressed.…”

Section: Discussionmentioning

confidence: 99%

Proteolytic Processing of Neuregulin 2

Czarnek

Bereta

2019

Mol Neurobiol

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Neuregulin 2 (NRG2) belongs to the EGF family of growth factors. Most of this family members require proteolytic cleavage to liberate their ectodomains capable of binding and activating their cognate ErbB receptors. To date, most of the studies investigating proteolytic processing of neuregulins focused on NRG1, which was shown to undergo ectodomain shedding by several ADAM proteases and BACE1 and the remaining fragment was further cleaved by γ-secretase. Recently, NRG2 attracted more attention due to its role in the neurogenesis and modulation of behaviors associated with psychiatric disorders. In this study, we used genetic engineering methods to identify proteases involved in proteolytic processing of murine NRG2. Using non-neuronal cell lines as well as cultures of primary hippocampal neurons, we demonstrated that the major proteases responsible for releasing NRG2 ectodomain are ADAM10 and BACE2. Co-expression of NRG2 and BACE2 in neurons of certain brain structures including medulla oblongata and cerebellar deep nuclei was confirmed via immunohistochemical staining. The cleavage of NRG2 by ADAM10 or BACE2 generates a C-terminal fragment that serves as a substrate for γ-secretase. We also showed that murine NRG2 is subject to post-translational modifications, substantial glycosylation of its extracellular part, and phosphorylation of the cytoplasmic tail.

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“…First, our recent study demonstrated that the binding of clusterin to the juxtamembrane helix (JH) of APP triggers BACE2-mediated β-cleavage of APP, indicating that BACE2 has comparable β-secretase activity to that of BACE1. Both BACE2 and clusterin are elevated in aged mouse brains, indicating that increased clusterin in the elderly may facilitate the β-secretase activity of BACE2, contributing to the pathogenesis of AD [8]. In addition, increased BACE2 expression and activity are detected in the neurons of AD brains [9].…”

Section: Introductionmentioning

confidence: 99%

RCAN1 Inhibits BACE2 Turnover by Attenuating Proteasome-Mediated BACE2 Degradation

Qiu

Wang

et al. 2020

BioMed Research International

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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.

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BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis

Cited by 59 publications

References 59 publications

BACE2 degradation is mediated by both the proteasome and lysosome pathways

BACE2 degradation is mediated by both the proteasome and lysosome pathways

Proteolytic Processing of Neuregulin 2

RCAN1 Inhibits BACE2 Turnover by Attenuating Proteasome-Mediated BACE2 Degradation

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