The amyloid precursor protein (APP) is a type I transmembrane protein with unknown physiological function but potential impact in neurodegeneration. The current study demonstrates that APP signals to the nucleus causing the generation of aggregates consisting of its adapter protein FE65, the histone acetyltransferase TIP60 and the tumour suppressor proteins p53 and PML. APP C-terminal (APP-CT50) complexes co-localize and co-precipitate with p53 and PML. The PML nuclear body generation is induced and fusion occurs over time depending on APP signalling and STED imaging revealed active gene expression within the complex. We further show that the nuclear aggregates of APP-CT50 fragments together with PML and FE65 are present in the aged human brain but not in cerebral organoids differentiated from iPS cells. Notably, human Alzheimer’s disease brains reveal a highly significant reduction of these nuclear aggregates in areas with high plaque load compared to plaque-free areas of the same individual. Based on these results we conclude that APP-CT50 signalling to the nucleus takes place in the aged human brain and is involved in the pathophysiology of AD.

中文翻译：

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淀粉样前体蛋白提高具有高斑块负荷的人海马区早幼粒细胞白血病核体的融合

淀粉样前体蛋白 (APP) 是一种 I 型跨膜蛋白，生理功能未知，但对神经变性有潜在影响。目前的研究表明，APP 向细胞核发出信号，导致产生由其衔接蛋白 FE65、组蛋白乙酰转移酶 TIP60 和肿瘤抑制蛋白 p53 和 PML 组成的聚集体。APP C 端 (APP-CT50) 复合物与 p53 和 PML 共定位和共沉淀。PML 核体生成被诱导并随着时间的推移发生融合，这取决于 APP 信号和 STED 成像显示复合物中的活跃基因表达。我们进一步表明，APP-CT50 片段与 PML 和 FE65 的核聚集体存在于老龄人脑中，但不存在于从 iPS 细胞分化的脑类器官中。尤其，人类阿尔茨海默病大脑显示，与同一个体的无斑块区域相比，具有高斑块负荷的区域中这些核聚集体显着减少。基于这些结果，我们得出结论，向细胞核发出 APP-CT50 信号发生在衰老的人脑中，并参与 AD 的病理生理学。