Aging is the biggest risk factor for the development of Alzheimer’s disease (AD). Here, we performed a whole-genome CRISPR screen to identify regulators of neuronal age and show that the neddylation pathway regulates both cellular age and AD neurodegeneration in a human stem cell model. Specifically, we demonstrate that blocking neddylation increased cellular hallmarks of aging and led to an increase in Tau aggregation and phosphorylation in neurons carrying the APP^swe/swe mutation. Aged APP^swe/swe but not isogenic control neurons also showed a progressive decrease in viability. Selective neuronal loss upon neddylation inhibition was similarly observed in other isogenic AD and in Parkinson’s disease (PD) models, including PSEN^M146V/M146V cortical and LRRK2^{G2019S/G2019S} midbrain dopamine neurons, respectively. This study indicates that cellular aging can reveal late-onset disease phenotypes, identifies new potential targets to modulate AD progression, and describes a strategy to program age-associated phenotypes into stem cell models of disease.

衰老是阿尔茨海默病（AD）发展的最大危险因素。在这里，我们进行了全基因组 CRISPR 筛选，以确定神经元年龄的调节因子，并表明neddylation 途径在人类干细胞模型中调节细胞年龄和 AD 神经变性。具体来说，我们证明阻断neddylation会增加细胞衰老特征，并导致携带APP ^swe/swe突变的神经元中Tau聚集和磷酸化增加。老化的 APP ^swe/swe但非同基因对照神经元也显示出活力逐渐下降。在其他同基因 AD 和帕金森病 (PD) 模型中，类似地观察到了 neddylation 抑制后的选择性神经元丢失，分别包括 PSEN ^M146V/M146V皮质和 LRRK2 ^{G2019S /G2019S}中脑多巴胺神经元。这项研究表明，细胞衰老可以揭示迟发性疾病表型，确定调节 AD 进展的新潜在靶标，并描述了将与年龄相关的表型编程到疾病干细胞模型中的策略。