CDK3はアルツハイマー病における神経細胞死と脳萎縮を誘発する

Progressive neuronal loss and brain atrophy are principal determinants of cognitive decline in Alzheimer's disease (AD), yet most mouse models fail to recapitulate these features. Here we identify cyclin-dependent kinase 3 (CDK3) as a key driver of neurodegeneration in AD. CDK3 is elevated in human AD brains and correlates with disease severity. As laboratory mice carry a nonfunctional Cdk3 mutation, we generated two models with restored CDK3 activity and then crossed to AD backgrounds. Both models exhibited substantial neuronal loss, hippocampal atrophy, and cognitive deficits. Single-nucleus RNA sequencing revealed neurons simultaneously activating cell cycle and cell death pathways, indicating cell cycle reentry-induced death. Proteomics implicated synaptic proteins as CDK3 substrates. Finally, we developed BMX330, an inhibitor of CDK3, which mitigated neuronal death and rescued cognitive decline in CDK3-restored AD mice. These findings position CDK3 as a therapeutic target and provide pathologically relevant AD models.