| 描述信息 |
The brain atrophy induced by neuronal loss is the most proximal cause of human Alzheimer's disease (AD). Unfortunately, in current rodent AD models, neuronal cell death is virtually absent. Here, we report that Cyclin dependent kinase 3 (CDK3), which drives cell cycle re-entry from G0 to G1, is highly expresses in AD patients' brain, and positively correlates with AD Braak stage and frontal atrophy. Cell cycle reentry induces post-mitotic neuronal death (CRND), most of the rodent laboratory mouse lines have a stop-codon mutation in Cdk3 gene. We generated transgenic mice with neuron-specific expression of human CDK3 overexpression or mouse Cdk3 engineered to remove the premature termination codon (Cdk3(561DM)). These lines were crossed with two classic AD mouse models: 5xFAD and Tau-PS19 mice. Exogenous hCDK3 or endogenous mCdk3 expression both induced massive neuronal death and hippocampal atrophy, accompanied by impairments in LTP and cognition in AD mice. Single-nucleus RNA sequencing reveals dramatic cell cycle activated neurons which are undergoing apoptosis, necroptosis and ferroptosis. We also screened and developed a CDK3 kinase inhibitor, BMX330, which alleviated neuronal death and cognitive impairments in hCDK3-overexpressing mice. Proteomics and phosphoproteomic analyses of hCDK3 substrates point to CRND and synaptic dysfunctions as main drivers of CDK3 mediated neuronal loss. Our findings provide deeper insights into the neuronal death mechanism of AD and establish two new AD mouse models that faithfully capture the neurodegeneration phenotype typically missing in most rodent models. These models have the potential to jumpstart new AD research and drug discovery. |
