Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease.
Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease.
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DOI：
10.1111/acel.12791
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发表时间：
2018-08
期刊：
影响因子：
7.8
通讯作者：
LaFerla FM
中科院分区：
文献类型：
--
作者：
Baglietto-Vargas D;Prieto GA;Limon A;Forner S;Rodriguez-Ortiz CJ;Ikemura K;Ager RR;Medeiros R;Trujillo-Estrada L;Martini AC;Kitazawa M;Davila JC;Cotman CW;Gutierrez A;LaFerla FM
阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，其损害记忆并导致认知和精神缺陷。新的证据表明，AD是一种突触功能障碍性疾病，尽管这些缺陷的分子和细胞机制仍有待阐明。确定早期突触缺陷的时间和性质对于了解疾病的进展和确定治疗干预的有效靶点至关重要。使用单突触功能和形态学分析，我们发现在AD小鼠模型中，介导中枢神经系统（CNS）中快速突触能突触传递的AMPA信号传导在疾病过程的早期受到损害。AMPA信号的下降与肌动蛋白细胞骨架完整性的变化有关，这改变了树突棘的数量和结构。AMPA功能障碍和脊柱改变与可溶性而非不溶性Aβ和tau物质的存在相关。特别是，我们证明了这些突触损伤可以通过Aβ免疫治疗来减轻。总之，我们的数据表明，AMPA信号和细胞骨架过程的改变发生在AD的早期。最重要的是，这些缺陷可以通过Aβ免疫治疗来预防，这表明现有的治疗方法，如果早期使用，可以带来功能性益处。
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single‐synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aβ and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aβ immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aβ immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.
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影响因子：
2.7
作者：
Clark JK;Furgerson M;Crystal JD;Fechheimer M;Furukawa R;Wagner JJ
通讯作者：
Wagner JJ
影响因子：
4.7
作者：
Baglietto-Vargas D;Chen Y;Suh D;Ager RR;Rodriguez-Ortiz CJ;Medeiros R;Myczek K;Green KN;Baram TZ;LaFerla FM
通讯作者：
LaFerla FM
影响因子：
15.1
作者：
Lemere CA
通讯作者：
Lemere CA
DOI：
10.1073/pnas.1012851108
发表时间：
2010-12-28
影响因子：
11.1
作者：
Caccamo, Antonella;Maldonado, Monica A.;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
DOI：
10.1523/jneurosci.2775-12.2012
发表时间：
2012-11-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lauritzen I;Pardossi-Piquard R;Bauer C;Brigham E;Abraham JD;Ranaldi S;Fraser P;St-George-Hyslop P;Le Thuc O;Espin V;Chami L;Dunys J;Checler F
通讯作者：
Checler F