Neurite deficits and synaptic dysfunction contribute to cognitive impairments in Alzheimer’s disease (AD). However, the underlying molecular mechanisms remain unclear. Here, we show that γ-adducin, a cytoskeleton-associated protein that assembles the spectrin-actin framework, is cleaved by a lysosomal cysteine proteinase named asparagine endopeptidase (AEP). AEP is upregulated and activated during aging and cleaves γ-adducin at N357, disrupting spectrin-actin assembly. Moreover, γ-adducin (1-357) fragment downregulates the expression of Rac2, leading to defects in neurite outgrowth. Expression of the γ-adducin (1-357) fragment in the hippocampus of tau P301S transgenic mice resulted in significant AD-like pathology and cognitive deficits. In summary, AEP-mediated fragmentation of γ-adducin plays a vital role in AD. Blocking the activity of AEP might be a novel therapeutic target for AD.

神经突缺陷和突触功能障碍导致阿尔茨海默病 (AD) 的认知障碍。然而，潜在的分子机制仍不清楚。在这里，我们展示了 γ-内引蛋白，一种组装 Spectrin-actin 框架的细胞骨架相关蛋白，被一种名为天冬酰胺内肽酶 (AEP) 的溶酶体半胱氨酸蛋白酶切割。AEP 在衰老过程中被上调和激活，并在 N357 处切割 γ-内收蛋白，从而破坏血影蛋白-肌动蛋白的组装。此外，γ-adducin (1-357) 片段下调 Rac2 的表达，导致神经突生长缺陷。tau P301S 转基因小鼠海马中 γ-adducin (1-357) 片段的表达导致显着的 AD 样病理和认知缺陷。总之，AEP 介导的 γ-内引蛋白片段化在 AD 中起着至关重要的作用。