Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis
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...
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| Language: | English |
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BMC
2024-12-01
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| Series: | Molecular Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s13024-024-00789-7 |
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| author | Lingliang Zhang Lingling Huang Yuhang Zhou Jian Meng Liang Zhang Yunqiang Zhou Naizhen Zheng Tiantian Guo Shanshan Zhao Zijie Wang Yuanhui Huo Yingjun Zhao Xiao-fen Chen Honghua Zheng David M. Holtzman Yun-wu Zhang |
| author_facet | Lingliang Zhang Lingling Huang Yuhang Zhou Jian Meng Liang Zhang Yunqiang Zhou Naizhen Zheng Tiantian Guo Shanshan Zhao Zijie Wang Yuanhui Huo Yingjun Zhao Xiao-fen Chen Honghua Zheng David M. Holtzman Yun-wu Zhang |
| author_sort | Lingliang Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-32ed5d0d0809434eb92ab41921cbf04c |
| institution | DOAJ |
| issn | 1750-1326 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-32ed5d0d0809434eb92ab41921cbf04c2025-08-20T02:40:17ZengBMCMolecular Neurodegeneration1750-13262024-12-0119112310.1186/s13024-024-00789-7Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosisLingliang Zhang0Lingling Huang1Yuhang Zhou2Jian Meng3Liang Zhang4Yunqiang Zhou5Naizhen Zheng6Tiantian Guo7Shanshan Zhao8Zijie Wang9Yuanhui Huo10Yingjun Zhao11Xiao-fen Chen12Honghua Zheng13David M. Holtzman14Yun-wu Zhang15Xiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityXiamen 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 UniversityDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of MedicineXiamen 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 UniversityAbstract 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.https://doi.org/10.1186/s13024-024-00789-7β-amyloidAlzheimer’s diseaseC1qCD2APCSF1RDisease-associated microglia |
| spellingShingle | Lingliang Zhang Lingling Huang Yuhang Zhou Jian Meng Liang Zhang Yunqiang Zhou Naizhen Zheng Tiantian Guo Shanshan Zhao Zijie Wang Yuanhui Huo Yingjun Zhao Xiao-fen Chen Honghua Zheng David M. Holtzman Yun-wu Zhang Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis Molecular Neurodegeneration β-amyloid Alzheimer’s disease C1q CD2AP CSF1R Disease-associated microglia |
| title | Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis |
| title_full | Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis |
| title_fullStr | Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis |
| title_full_unstemmed | Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis |
| title_short | Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis |
| title_sort | microglial cd2ap deficiency exerts protection in an alzheimer s disease model of amyloidosis |
| topic | β-amyloid Alzheimer’s disease C1q CD2AP CSF1R Disease-associated microglia |
| url | https://doi.org/10.1186/s13024-024-00789-7 |
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