阿尔茨海默病风险基因 CD2AP 通过重塑 F-肌动蛋白在树突棘中发挥作用。

IF 4.4 2区 医学 Q1 NEUROSCIENCES
Farzaneh S Mirfakhar, Jorge Castanheira, Raquel Domingues, José S Ramalho, Cláudia Guimas Almeida
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引用次数: 0

摘要

CD2AP 被确定为晚发性阿尔茨海默病(LOAD)的遗传风险因素。然而,目前还不清楚 CD2AP 是如何导致阿尔茨海默病记忆缺陷背后的突触功能障碍的。我们已经证明,CD2AP功能缺失会增加β淀粉样蛋白(Aβ)内含物的产生,但它是否会导致突触功能障碍还不得而知。由于CD2AP是一种肌动蛋白结合蛋白,它也可能在富含F-肌动蛋白的树突棘中发挥作用,而树突棘是兴奋性突触后区室。在这里,我们证明了 CD2AP 与 F-肌动蛋白共定位在小鼠雌雄原代皮质神经元的树突棘中。细胞自主消耗 CD2AP 会特异性地降低棘突密度和体积,从而导致突触形成和神经元网络活动的功能性减少。突触后重新表达 CD2AP(而非阻断 Aβ 生成)足以挽救脊柱密度。CD2AP过表达会增加脊柱密度、体积和突触形成,而罕见的LOAD CD2AP突变会诱导异常的F-肌动蛋白脊柱样突起,但不产生功能性突触。CD2AP 控制突触后肌动蛋白的周转,CD2AP 的 LOAD 突变会降低 F-肌动蛋白的动态性。我们的数据支持 CD2AP 风险变异可能会通过扰乱肌动蛋白动态来破坏脊柱的形成和生长,从而导致 LOAD 突触功能障碍。我们的研究揭示了 CD2AP 是一种新的突触蛋白,并建立了 CD2AP 的 LOAD 遗传变异与突触功能障碍之间的联系,而不依赖于 beta 淀粉样蛋白的积累。这项研究为 CD2AP 介导的 AD 易感性提供了一种解释。此外,我们还发现,控制 CD2AP 对脊髓 F-肌动蛋白的影响可能是治疗 LOAD 的一个潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Alzheimer's disease risk gene CD2AP functions in dendritic spines by remodeling F-actin.

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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来源期刊
Journal of Neuroscience
Journal of Neuroscience 医学-神经科学
CiteScore
9.30
自引率
3.80%
发文量
1164
审稿时长
12 months
期刊介绍: JNeurosci (ISSN 0270-6474) is an official journal of the Society for Neuroscience. It is published weekly by the Society, fifty weeks a year, one volume a year. JNeurosci publishes papers on a broad range of topics of general interest to those working on the nervous system. Authors now have an Open Choice option for their published articles
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