| First Author | Xia Y | Year | 2021 |
| Journal | Prog Neurobiol | Volume | 204 |
| Pages | 102113 | PubMed ID | 34166772 |
| Mgi Jnum | J:368419 | Mgi Id | MGI:8215257 |
| Doi | 10.1016/j.pneurobio.2021.102113 | Citation | Xia Y, et al. (2021) Delta- and beta- secretases crosstalk amplifies the amyloidogenic pathway in Alzheimer's disease. Prog Neurobiol 204:102113 |
| abstractText | 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-beta (Abeta) 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 Abeta production, facilitating AD pathologies and cognitive impairments in APP/PS1 AD mouse model. Uncleavable BACE1 (N294A) inhibits delta-secretase activity and Abeta 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. |
