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The raw proteomic data of overexpressing hCDK3 in neuron

ABSTRACT: The neuronal loss induced-brain atrophy is the direct cause of Alzheimer’s disease (AD), but hardly can be observed in rodent AD models, and the underlying mechanisms remain unclear. Cell cycle reentry induces post-mitotic neuronal death (CRND). Here, we found that Cyclin dependent kinase 3 (CDK3) which drives cell cycle re-entry from G0 to G1 phase transition highly expresses in AD patients’ brain, and positively correlates with AD Braak stage and frontal atrophy. However, most of the rodent laboratory mouse lines have a stop-code mutation in Cdk3 gene. We generated neuronal specifically human CDK3 overexpression transgenic mice and the premature termination codon mutation correction knock-in mice (Cdk3(561DM)), and crossed them 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, accompanying with exacerbated impairments of LTP and cognition in AD mice. We also screened and developed a CDK3 kinase inhibitor BMX330, which alleviated neuronal death and cognitive impairments in hCDK3-overexpressed mice. The multi proteomics and phosphoproteomics analyses of hCDK3 substrates further revealed that the CRND and synaptic dysfunctions are involved in CDK3 mediated neuronal loss. Our finding not only provide new evidence on the neuronal death mechanism of AD, but also created new AD mouse models which exhibit comprehensive AD-relevant pathological characteristics, particularly, neuronal death and brain atrophy. They may serve as useful tools in facilitating both AD research and drug discovery.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Cerebral Cortex Neuron, Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Shuzhong Wang

LAB HEAD: Jie Zhang

PROVIDER: PXD063971 | Pride | 2025-10-27

REPOSITORIES: Pride

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Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a progressive cognitive decline. Epidemiological studies have suggested a protective role of caffeine consumption against age-related cognitive impairments and the risk of developing AD. Effects of caffeine have been particularly ascribed to its ability to block adenosine A2A receptors (A2ARs). Early pathological upregulation of these receptors by neurons is thought to be involved in the development of synaptic and memory deficits in AD but this remains ill-defined. To tackle this question, we employed a novel transgenic mouse model allowing to promote a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice, developing AD-like amyloidogenesis. This new model was used to determine the impact of an early upregulation of A2AR on the progression of neuropathological lesions, associated behavior and underlying mechanisms in APP/PS1 mice. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioral changes were not linked to major change in the development of amyloid pathology but rather associate with an increased p-tau at neuritic plaques. Moreover, proteomic and transcriptomic analysis coupled to quantitative immunofluorescence studies indicated that neuronal impairment of the receptor promoted both neuronal- and non-neuronal autonomous alterations i.e. loss of excitatory synapses and neuroinflammatory response, respectively, both presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction as seen in the brain of patients contributes to AD pathogenesis, favoring synaptic deficits promoted by both amyloid (this study) and tau lesions (our previous study). In addition to provide new insights into the complex pathophysiology of AD, the present findings underscore the potential of A2AR as a relevant therapeutic target for mitigating early synaptic loss in this neurodegenerative disorder.

			Action	DRS
	APEX2-CDK3.xlsx	Xlsx
	CDK3-1.d.zip	Other
	CDK3-2.d.zip	Other
	CDK3-3.d.zip	Other
	Con-1.d.zip	Other

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The raw proteomic data of overexpressing hCDK3 in neuron

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