小胶质细胞CD2AP缺乏在淀粉样变性的阿尔茨海默病模型中发挥保护作用。

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

作者信息

Zhang Lingliang, Huang Lingling, Zhou Yuhang, Meng Jian, Zhang Liang, Zhou Yunqiang, Zheng Naizhen, Guo Tiantian, Zhao Shanshan, Wang Zijie, Huo Yuanhui, Zhao Yingjun, Chen Xiao-Fen, Zheng Honghua, Holtzman David M, Zhang Yun-Wu

机构信息

Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.

出版信息

Mol Neurodegener. 2024 Dec 18;19(1):95. doi: 10.1186/s13024-024-00789-7.

DOI:10.1186/s13024-024-00789-7

PMID:39695808

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11658232/

Abstract

BACKGROUND

The 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.

METHODS

CD2AP 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.

RESULTS

We 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 Aβ 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 Aβ 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.

CONCLUSIONS

Our results demonstrate that CD2AP regulates microgliosis and identify a protective function of microglial CD2AP deficiency against Aβ deposition, suggesting the importance of detailed investigation of AD-associated genes in different brain cells for thoroughly understanding their exact contribution to AD.

摘要

背景

CD2相关蛋白（CD2AP）最初在外周免疫细胞中被鉴定出来，可调节细胞骨架和蛋白质运输。CD2AP基因中的单核苷酸多态性（SNP）与阿尔茨海默病（AD）相关。然而，CD2AP的功能作用，尤其是其在AD发病过程中在小胶质细胞中的作用，仍不清楚。

方法

研究了原代培养细胞和5xFAD小鼠中CD2AP蛋白水平。将小胶质细胞CD2AP缺陷小鼠与5xFAD小鼠杂交，对后代进行神经病理学评估、行为测试、电生理学、RNA测序、高尔基染色和生物化学分析。还分离了原代小胶质细胞以评估其摄取和形态变化。

结果

我们发现CD2AP在小胶质细胞中大量表达，且在AD患者大脑和病理阶段的5xFAD模型小鼠大脑中其水平升高。我们证明小胶质细胞中CD2AP单倍体不足显著减轻认知和突触缺陷，减弱小胶质细胞对Aβ的反应以及疾病相关小胶质细胞（DAM）的形成，并减轻5xFAD小鼠的突触损失。我们表明CD2AP缺陷的小胶质细胞摄取能力受损。此外，我们发现CD2AP表达与补体C1q的表达呈正相关，补体C1q对突触吞噬和响应Aβ沉积形成DAM很重要。此外，我们揭示CD2AP与集落刺激因子1受体（CSF1R）相互作用并调节CSF1R细胞表面水平，这可能进一步影响C1q表达。