Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
Nat Commun. 2013;4:2250. doi: 10.1038/ncomms3250.
Defects in endosomal sorting have been implicated in Alzheimer's disease. Endosomal traffic is largely controlled by phosphatidylinositol-3-phosphate, a phosphoinositide synthesized primarily by lipid kinase Vps34. Here we show that phosphatidylinositol-3-phosphate is selectively deficient in brain tissue from humans with Alzheimer's disease and Alzheimer's disease mouse models. Silencing Vps34 causes an enlargement of neuronal endosomes, enhances the amyloidogenic processing of amyloid precursor protein in these organelles and reduces amyloid precursor protein sorting to intraluminal vesicles. This trafficking phenotype is recapitulated by silencing components of the ESCRT (Endosomal Sorting Complex Required for Transport) pathway, including the phosphatidylinositol-3-phosphate effector Hrs and Tsg101. Amyloid precursor protein is ubiquitinated, and interfering with this process by targeted mutagenesis alters sorting of amyloid precursor protein to the intraluminal vesicles of endosomes and enhances amyloid-beta peptide generation. In addition to establishing phosphatidylinositol-3-phosphate deficiency as a contributing factor in Alzheimer's disease, these results clarify the mechanisms of amyloid precursor protein trafficking through the endosomal system in normal and pathological states.
内体分选缺陷与阿尔茨海默病有关。内体运输主要受磷脂酰肌醇-3-磷酸（PI3P）控制，PI3P 主要由脂质激酶 Vps34 合成。本文作者发现，PI3P 在阿尔茨海默病患者和阿尔茨海默病小鼠模型的脑组织中选择性缺乏。沉默 Vps34 会导致神经元内体增大，增强这些细胞器中淀粉样前体蛋白的淀粉样生成加工，并减少淀粉样前体蛋白向腔内小泡的分选。沉默 ESCRT（Endosomal Sorting Complex Required for Transport）途径的组分，包括 PI3P 效应因子 Hrs 和 Tsg101，可再现这种运输表型。淀粉样前体蛋白被泛素化，通过靶向突变改变这个过程会改变淀粉样前体蛋白向腔内小泡的分选，并增强β淀粉样肽的生成。这些结果不仅证实了 PI3P 缺陷是阿尔茨海默病的一个致病因素，还阐明了在正常和病理状态下淀粉样前体蛋白通过内体系统运输的机制。
