Microglial CD2AP deficiency exerts protection in an Alzheimer's disease model of amyloidosis

被引：0

作者：

Zhang, Lingliang ^{[1
,2
]}

Huang, Lingling ^{[1
,2
]}

Zhou, Yuhang ^{[1
,2
]}

Meng, Jian ^{[1
,2
]}

Zhang, Liang ^{[1
,2
]}

Zhou, Yunqiang ^{[1
,2
]}

Zheng, Naizhen ^{[1
,2
]}

Guo, Tiantian ^{[1
,2
]}

Zhao, Shanshan ^{[1
,2
]}

Wang, Zijie ^{[1
,2
]}

Huo, Yuanhui ^{[1
,2
]}

Zhao, Yingjun ^{[1
,2
]}

Chen, Xiao-fen ^{[1
,2
]}

Zheng, Honghua ^{[1
,2
]}

Holtzman, David M. ^{[3
]}

Zhang, Yun-wu ^{[1
,2
]}

机构：

[1] Xiamen Univ, Affiliated Hosp 1, Xiamen Key Lab Brain Ctr, Xiamen 361102, Fujian, Peoples R China

[2] Xiamen Univ, Inst Neurosci, Sch Med, Fujian Prov Key Lab Neurodegenerat Dis & Aging Res, Xiamen 361102, Fujian, Peoples R China

[3] Washington Univ, Hope Ctr Neurol Disorders, Knight Alzheimers Dis Res Ctr, Dept Neurol,Sch Med, St Louis, MO USA

来源：

MOLECULAR NEURODEGENERATION | 2024年 / 19卷 / 01期

基金：

中国国家自然科学基金;

关键词：

beta-amyloid; Alzheimer's disease; C1q; CD2AP; CSF1R; Disease-associated microglia; Microglia; COLONY-STIMULATING FACTOR; MOUSE MODEL; APOLIPOPROTEIN-E; COMMON VARIANTS; CSF-1; RECEPTOR; A-BETA; BRAIN; EXPRESSION; NEURODEGENERATION; CELLS;

D O I：

10.1186/s13024-024-00789-7

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

BackgroundThe CD2-associated protein (CD2AP) was initially identified in peripheral immune cells and regulates cytoskeleton and protein trafficking. Single nucleotide polymorphisms (SNPs) in the CD2AP gene have been associated with Alzheimer's disease (AD). However, the functional role of CD2AP, especially its role in microglia during AD onset, remains elusive.MethodsCD2AP protein levels in cultured primary cells and in 5xFAD mice was studied. Microglial CD2AP-deficient mice were crossed with 5xFAD mice and the offspring were subjected to neuropathological assessment, behavioral tests, electrophysiology, RNA-seq, Golgi staining, and biochemistry analysis. Primary microglia were also isolated for assessing their uptake and morphology changes.ResultsWe find that CD2AP is abundantly expressed in microglia and its levels are elevated in the brain of AD patients and the 5xFAD model mice at pathological stages. We demonstrate that CD2AP haploinsufficiency in microglia significantly attenuates cognitive and synaptic deficits, weakens the response of microglia to A beta and the formation of disease-associated microglia (DAM), and alleviates synapse loss in 5xFAD mice. We show that CD2AP-deficient microglia exhibit compromised uptake ability. In addition, we find that CD2AP expression is positively correlated with the expression of the complement C1q that is important for synapse phagocytosis and the formation of DAM in response to A beta deposition. Moreover, we reveal that CD2AP interacts with colony stimulating factor 1 receptor (CSF1R) and regulates CSF1R cell surface levels, which may further affect C1q expression.ConclusionsOur results demonstrate that CD2AP regulates microgliosis and identify a protective function of microglial CD2AP deficiency against A beta deposition, suggesting the importance of detailed investigation of AD-associated genes in different brain cells for thoroughly understanding their exact contribution to AD.

引用

页数：23

共 92 条

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