Delta- and beta- secretases crosstalk amplifies the amyloidogenic pathway in Alzheimer's disease. (September 2021)

• Record Type: Journal Article
• Authors: Xia, Yiyuan; Wang, Zhi-Hao; Zhang, Zhentao; Liu, Xia; Yu, Shan Ping; Wang, Jian-Zhi; Wang, Xiao-Chuan; Ye, Keqiang
• Is Part Of: Progress in neurobiology. Volume 204(2021)
• Publication Date: 2021-09
• Subjects: Delta-secretase -- Beta-secretase -- Aβ -- Senile plaques -- Alzheimer's disease; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2021.102113
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: Delta-secretase interacts with BACE1 and cleaves it in the endo-lysosomes. BACE1 N294 fragment displays higher enzymatic activity than full-length counterpart, stimulating δ-secretase activation. BACE1 N294 fragment is secreted extracellularly and associates with senile plaques. BACE1 N294 is active even under pH 7.4, indicating that it may cleave APP in the extracellular space. Abstract: Asparagine endopeptidase (AEP), a newly identified delta-secretase, simultaneously cleaves both APP and Tau, promoting Alzheimer's disease (AD) pathologies. However, its pathological role in AD remains incompletely understood. Here we show that delta-secretase cleaves BACE1, a rate-limiting protease in amyloid-β (Aβ) generation, escalating its enzymatic activity and enhancing senile plaques deposit in AD. Delta-secretase binds BACE1 and cuts it at N294 residue in an age-dependent manner and elevates its protease activity. The cleaved N-terminal motif is active even under neutral pH and associates with senile plaques in human AD brains. Subcellular fractionation reveals that delta-secretase and BACE1 reside in the endo-lysosomes. Interestingly, truncated BACE1 enzymatic domain (1-294) augments delta-secretase enzymatic activity and accelerates Aβ production, facilitating AD pathologies and cognitive impairments in APP/PS1 AD mouse model. Uncleavable BACE1 (N294A) inhibits delta-secretase activity and Aβ production and decreases AD pathologies in 5XFAD mice, ameliorating cognitive dysfunctions. Hence, delta- and beta- secretases' crosstalk aggravates each other's roles in AD pathogenesis.