CDK3 induces neuronal death and brain atrophy in Alzheimer's disease

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.