CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activation  

作　　者：Yan-Yan Xue Zhe-Sheng Zhang Rong-Rong Lin Hui-Fen Huang Ke-Qing Zhu Dian-Fu Chen Zhi-Ying Wu Qing-Qing Tao 

机构地区：[1]Department of Neurology,The Second Affiliated Hospital,Zhejiang University School of Medicine and Liangzhu Laboratory,88 Jiefang Road,Hangzhou 310009,China [2]National Health and Disease Human Brain Tissue Resource Center and Department of Pathology,School of Medicine,Zhejiang University,Hangzhou 310058,China [3]MOE Frontier Science Center for Brain Science and Brain-Machine Integration,School of Brain Science and Brain Medicine,Zhejiang University,Hangzhou 310058,China [4]CAS Center for Excellence in Brain Science and Intelligence Technology,Shanghai 200031,China

出　　处：《Translational Neurodegeneration》2024年第1期93-113,共21页转化神经变性病(英文)

基　　金：supported by grants from the National Natural Science Foundation of China(81970998);the Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects(Nos.2021ZD0201103 and 2021ZD0201803);the Key R&D Program of Zhejiang(2024SSYS0018).

摘　　要：Background Alzheimer’s disease(AD)is the most common form of neurodegenerative disorder,which is characterized by a decline in cognitive abilities.Genome-wide association and clinicopathological studies have demonstrated that the CD2-associated protein(CD2AP)gene is one of the most important genetic risk factors for AD.However,the precise mechanisms by which CD2AP is linked to AD pathogenesis remain unclear.Methods The spatiotemporal expression pattern of CD2AP was determined.Then,we generated and characterized an APP/PS1 mouse model with neuron-specific Cd2ap deletion,using immunoblotting,immunofluorescence,enzyme-linked immunosorbent assay,electrophysiology and behavioral tests.Additionally,we established a stable CD2AP-knockdown SH-SY5Y cell line to further elucidate the specific molecular mechanisms by which CD2AP contributes to AD pathogenesis.Finally,the APP/PS1 mice with neuron-specific Cd2ap deletion were treated with an inhibitor targeting the pathway identified above to further validate our findings.Results CD2AP is widely expressed in various regions of the mouse brain,with predominant expression in neurons and vascular endothelial cells.In APP/PS1 mice,neuronal knockout of Cd2ap significantly aggravated tau pathology,synaptic impairments and cognitive deficits.Mechanistically,the knockout of Cd2ap activated p38 mitogen-activated protein kinase(MAPK)signaling,which contributed to increased tau phosphorylation,synaptic injury,neuronal apoptosis and cognitive impairment.Furthermore,the phenotypes of neuronal Cd2ap knockout were ameliorated by a p38 MAPK inhibitor.Conclusion Our study presents the first in vivo evidence that CD2AP deficiency exacerbates the phenotypes and pathology of AD through the p38 MAPK pathway,identifying CD2AP/p38 MAPK as promising therapeutic targets for AD.

关 键 词：Alzheimer’s disease CD2AP P38 MAPK Synaptic injury Tau 

分 类 号：R69[医药卫生—泌尿科学]