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.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
左眼是为了记住你完成签到,获得积分10
刚刚
xh关闭了xh文献求助
3秒前
3秒前
4秒前
祖诗云完成签到,获得积分10
5秒前
科研通AI2S应助晓晓晓采纳,获得10
5秒前
活力元龙发布了新的文献求助10
6秒前
Akim应助呆小仙采纳,获得10
7秒前
8秒前
破伤疯发布了新的文献求助10
9秒前
10秒前
小蘑菇应助常常采纳,获得10
12秒前
YY完成签到,获得积分10
12秒前
13秒前
学就完了完成签到,获得积分10
13秒前
夕风残照发布了新的文献求助30
13秒前
14秒前
小满完成签到,获得积分10
17秒前
LionontheMars发布了新的文献求助10
18秒前
小蘑菇应助黑白骑士采纳,获得10
18秒前
18秒前
18秒前
彭于晏应助科研通管家采纳,获得20
18秒前
今后应助科研通管家采纳,获得30
18秒前
小二郎应助科研通管家采纳,获得10
18秒前
星辰大海应助科研通管家采纳,获得10
18秒前
乐乐应助科研通管家采纳,获得10
18秒前
大模型应助科研通管家采纳,获得10
18秒前
科研通AI2S应助科研通管家采纳,获得10
18秒前
脑洞疼应助科研通管家采纳,获得10
18秒前
学就完了发布了新的文献求助10
20秒前
桐桐应助BEST采纳,获得10
21秒前
加湿器应助于是真的采纳,获得30
21秒前
21秒前
活力元龙完成签到 ,获得积分10
24秒前
24秒前
可爱因子发布了新的文献求助10
24秒前
25秒前
cc完成签到,获得积分10
25秒前
jane发布了新的文献求助80
26秒前
高分求助中
Sustainability in Tides Chemistry 2000
The ACS Guide to Scholarly Communication 2000
Studien zur Ideengeschichte der Gesetzgebung 1000
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
Threaded Harmony: A Sustainable Approach to Fashion 810
Pharmacogenomics: Applications to Patient Care, Third Edition 800
Ожившие листья и блуждающие цветы. Практическое руководство по содержанию богомолов [Alive leaves and wandering flowers. A practical guide for keeping praying mantises] 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3079159
求助须知:如何正确求助?哪些是违规求助? 2731733
关于积分的说明 7520409
捐赠科研通 2380586
什么是DOI,文献DOI怎么找? 1262296
科研通“疑难数据库(出版商)”最低求助积分说明 611848
版权声明 597396