A protective role for APP in nuclear waste clearance via lysosomal exocytosis

Amyloid precursor protein (APP) is widely known for its role in Alzheimer’s disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological function remains incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.淀粉样前体蛋白（Amyloid Precursor Protein，APP）经蛋白水解加工生成β淀粉样肽，其在阿尔茨海默病（Alzheimer’s Disease，AD）发病机制中的作用已广为人知。然而，其生理功能仍未完全阐明。本研究揭示了全长APP在基因毒性应激下促进核源性碎屑清除的保护作用。在培养细胞与活体小鼠模型中，APP缺失会导致核废物积累、炎症加剧与细胞死亡，而APP过表达则可缓解这些不良效应。机制研究显示，APP可通过溶酶体胞吐作用促进核物质的胞外释放。与家族性阿尔茨海默病相关的APP突变体无法介导这一过程。与之一致的是，人类阿尔茨海默病患者的脑组织表现出核形态异常、胞质内核废物积累以及神经元内APP水平降低的特征。这些研究结果揭示了APP维持细胞核与细胞稳态的保守细胞机制，并提示核废物清除受损可能是神经退行性病变中一个未被充分重视的致病因素。