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.

天冬酰胺内肽酶 (AEP) 是一种新发现的 delta-secretase，它同时切割 APP 和 Tau，促进阿尔茨海默病 (AD) 病理。然而，其在 AD 中的病理作用仍未完全了解。在这里，我们表明 delta-secretase 切割 BACE1，一种淀粉样蛋白-β (Aβ) 生成中的限速蛋白酶，提高其酶活性并增强 AD 中的老年斑沉积。Delta-secretase 与 BACE1 结合并以年龄依赖性方式在 N294 残基处切割它并提高其蛋白酶活性。切割的 N 末端基序即使在中性 pH 值下也有活性，并与人类 AD 大脑中的老年斑相关。亚细胞分离显示 delta-secretase 和 BACE1 存在于内溶酶体中。有趣的是，截短的 BACE1 酶结构域 (1-294) 增强 delta-secretase 酶活性并加速 Aβ 产生，促进 APP/PS1 AD 小鼠模型中的 AD 病理和认知障碍。Uncleavable BACE1 (N294A) 抑制 delta-secretase 活性和 Aβ 产生并减少 5XFAD 小鼠的 AD 病理，改善认知功能障碍。因此，δ 和 β 分泌酶的串扰加剧了彼此在 AD 发病机制中的作用。