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

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.

• Authors: Yiyuan Xia, Zhi-Hao Wang, Zhentao Zhang, Xia Liu, Shan Ping Yu, Jian-Zhi Wang, Xiao-Chuan Wang, Keqiang Ye
• Journal: Progress in neurobiology (Prog Neurobiol) Vol. 204 Pg. 102113 (09 2021) ISSN: 1873-5118 [Electronic] England
• PMID: 34166772 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases

Topics

• Alzheimer Disease
• Amyloid Precursor Protein Secretases
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Animals
• Aspartic Acid Endopeptidases
• Mice
• Plaque, Amyloid