The Alzheimer's disease risk gene CD2AP functions in dendritic spines by remodeling F-actin

树突棘 突触 生物 突触后电位 细胞生物学 神经科学 肌动蛋白细胞骨架 细胞骨架 细胞 遗传学 受体 海马结构
作者
Farzaneh Sadat Mirfakhar,Jorge Castanheira,Raquel Domingues,José S. Ramalho,Cláudia Guimas Almeida
出处
期刊:The Journal of Neuroscience [Society for Neuroscience]
卷期号:: e1734232024-e1734232024
标识
DOI:10.1523/jneurosci.1734-23.2024
摘要

CD2AP was identified as a genetic risk factor for late-onset Alzheimer's disease (LOAD). However, it is unclear how CD2AP contributes to LOAD synaptic dysfunction underlying AD memory deficits. We have shown that loss of CD2AP function increases β-amyloid (Aβ) endocytic production, but it is unknown whether it contributes to synapse dysfunction. As CD2AP is an actin-binding protein, it may also function in F-actin-rich dendritic spines, which are the excitatory postsynaptic compartments. Here, we demonstrate that CD2AP colocalizes with F-actin in dendritic spines of primary mouse cortical neurons of both sexes. Cell-autonomous depletion of CD2AP specifically reduces spine density and volume, resulting in a functional decrease in synapse formation and neuronal network activity. Post-synaptic reexpression of CD2AP, but not blocking Aβ-production, is sufficient to rescue spine density. CD2AP overexpression increases spine density, volume, and synapse formation, while a rare LOAD CD2AP mutation induces aberrant F-actin spine-like protrusions without functional synapses. CD2AP controls postsynaptic actin turnover, with the LOAD mutation in CD2AP decreasing F-actin dynamicity. Our data support that CD2AP risk variants could contribute to LOAD synapse dysfunction by disrupting spine formation and growth by deregulating actin dynamics. Significance statement CD2AP is a candidate genetic risk factor of late-onset Alzheimer’s disease (LOAD) expressed in neurons with an unknown impact on synapse dysfunction, one of the causal LOAD mechanisms. Our research has revealed CD2AP as a new synaptic protein and established a connection between a LOAD genetic variant in CD2AP and synaptic dysfunction independent of beta-amyloid accumulation. This study suggests an explanation for the CD2AP-mediated predisposition to AD. Furthermore, we have found that controlling CD2AP's impact on spinal F-actin could be a potential target for therapeutic intervention against LOAD.

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