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) augme

SUBMITTER: Xia Y 

PROVIDER: S-EPMC8627568 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature