Yokomizo Midori, Sadek Michael, Williams Emily, Houser Mei C Q, Wieckiewicz Natalia, Torres Sebastian, Berezovska Oksana, Maesako Masato
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Cell Death Dis. 2025 Aug 9;16(1):604. doi: 10.1038/s41419-025-07934-0.
Mutations in the genes encoding APP, Presenilin-1 (PSEN1), and PSEN2 result in early-onset Alzheimer's disease (AD). Previous studies, using iPSC-derived neurons and/or knock-in mice, elucidated the characteristics of neurons expressing familial AD (fAD) mutations. Here, we employ biochemical and state-of-the-art fluorescence imaging assays and report the discovery of a unique subpopulation of wild-type neurons strikingly recapitulating key phenotypes previously identified in the fAD neurons, including the favored production of longer over shorter β-amyloid (Aβ) peptides, endo-lysosomal abnormalities, and increased vulnerability phenotypes in response to toxic insults. Importantly, mechanistic studies define inefficient γ-secretase and impaired endo-lysosomes as the upstream events of increased neuronal susceptibility. This discovery of the unique population of neurons with disease phenotypes would open a new avenue to develop novel therapeutics targeting neuronal vulnerability.
编码淀粉样前体蛋白（APP）、早老素-1（PSEN1）和早老素-2（PSEN2）的基因突变会导致早发性阿尔茨海默病（AD）。以往的研究利用诱导多能干细胞衍生的神经元和/或基因敲入小鼠，阐明了表达家族性AD（fAD）突变的神经元的特征。在此，我们采用生化和最先进的荧光成像分析方法，并报告发现了一个独特的野生型神经元亚群，该亚群惊人地重现了先前在fAD神经元中确定的关键表型，包括更倾向于产生更长而非更短的β-淀粉样蛋白（Aβ）肽、内溶酶体异常以及对毒性损伤的易损性增加表型。重要的是，机制研究将低效的γ-分泌酶和受损的内溶酶体定义为神经元易感性增加的上游事件。这一具有疾病表型的独特神经元群体的发现将为开发针对神经元易损性的新型疗法开辟一条新途径。
