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Cited by 13Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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

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Zhang, Lingliang, Huang, Lingling, Zhou, Yuhang, Meng, Jian, Zhang, Liang, Zhou, Yunqiang, Zheng, Naizhen, Guo, Tiantian +8 more·2024·Molecular Neurodegeneration
DOI 10.1186/s13024-024-00789-7PMC PMC11658232
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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.

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  • CD2AP interacts with the CSF1 receptor to regulate microgliosis in 5xFAD mice.

    “work focused on another AD risk gene involved in focal adhesion signaling, CD2AP , demon­ strated that CD2AP interacts with the CSF1 receptor to regulate microgliosis in 5xFAD mice (Zhang et al., 2024).”

    From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Zhang et al., 2024

    The Results (‘CD2AP modulates CSF1R function’; page not provided) verify an interaction between CD2AP and CSF1R and report reduced microgliosis in 5xFAD mice with microglial CD2AP haploinsufficiency. But the Results call CSF1R’s role in that reduction ‘indirect evidence,’ and the Discussion says the authors could not perform the rescue experiment needed to establish that CSF1R mediates the effect. The claim overstates the demonstrated mechanism. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Sorted by citations

Authors
Zhang, L., Huang, L., Zhou, Y., Meng, J., Zhang, L., Zhou, Y., Zheng, N., Guo, T., Zhao, S., Wang, Z., Huo, Y., Zhao, Y., Chen, X.-F., Zheng, H., Holtzman, D. M., & Zhang, Y.-W.
Affiliations
  • Xiamen University (CN)
  • Washington University in St. Louis (US)
Corresponding author
Zhang, Yun-wu
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2024-12-18
Volume
19
Issue
1
Pages
95-95
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-024-00789-7
PMC
PMC11658232
OpenAlex
W4405522935
Cited by
13
References
21
Citations by year
2026: 5 · 2025: 8
FWCI
2.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (U21A20361, 82130039)
  • Fundamental Research Funds for the Central Universities (20720220133)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
CD2AP, Alzheimer's disease, microglia, amyloid-beta, 5xFAD mice, disease-associated microglia, microglial activation, haploinsufficiency, synaptic loss, C1q, CSF1R, microglial phagocytosis, cognitive impairment, synaptic dysfunction
MeSH terms
Alzheimer Disease, Amyloidosis, Animals, Brain, Cytoskeletal Proteins, Disease Models, Animal, Humans, Mice, Transgenic, Microglia, Adaptor Proteins, Signal Transducing, Mice

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