Synapsin-caveolin-1 gene therapy preserves neuronal and synaptic morphology and prevents neurodegeneration in a mouse model of AD.
Synapsin-caveolin-1 gene therapy preserves neuronal and synaptic morphology and prevents neurodegeneration in a mouse model of AD.
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DOI：
10.1016/j.omtm.2021.03.021
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发表时间：
2021-06-11
期刊：
影响因子：
--
通讯作者：
Head BP
中科院分区：
文献类型：
--
作者：
Wang S;Leem JS;Podvin S;Hook V;Kleschevnikov N;Savchenko P;Dhanani M;Zhou K;Kelly IC;Zhang T;Miyanohara A;Nguyen P;Kleschevnikov A;Wagner SL;Trojanowski JQ;Roth DM;Patel HH;Patel PM;Head BP
阿尔茨海默病(AD)是老年人最常见的神经退行性变和认知功能障碍。识别减轻和逆转AD神经退行性变的分子信号可能被用于治疗。转基因AD小鼠(PSAPP)在9个月和11个月时分别表现出学习和记忆障碍，并伴随着小窝-1(Cav-1)的表达减少，小窝-1是突触和神经可塑性所必需的膜/脂筏(MLR)支架蛋白。3个月后，用腺相关病毒血清9型(AAV9)将突触素-Cav-1基因(SynCav1)导入PSAPP小鼠的海马神经元靶向基因治疗。双侧SynCav1基因治疗能够保留9和11个月龄PSAPP小鼠的MLRs轮廓、学习和记忆、海马树突状突起、突触超微结构和轴突髓鞘含量，而不依赖于减少有毒淀粉样沉积和星形胶质细胞增生。我们的数据表明，SynCav1基因治疗可能是AD的一种选择，并可能用于其他形式的未知病因的神经退行性变。研究结果表明，无论神经病理的病因如何，SynCav1都可以用于治疗零星疾病，或者与现有的药物或生物制剂结合使用，这些药物或生物制剂旨在针对与其他神经退行性疾病(AD、ALS、MS)相关的已知单基因候选。
Alzheimer’s disease (AD) is the most common form of neurodegeneration and cognitive dysfunction in the elderly. Identifying molecular signals that mitigate and reverse neurodegeneration in AD may be exploited therapeutically. Transgenic AD mice (PSAPP) exhibit learning and memory deficits at 9 and 11 months, respectively, with associated decreased expression of caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein necessary for synaptic and neuroplasticity. Neuronal-targeted gene therapy using synapsin-Cav-1 cDNA (SynCav1) was delivered to the hippocampus of PSAPP mice at 3 months using adeno-associated virus serotype 9 (AAV9). Bilateral SynCav1 gene therapy was able to preserve MLRs profile, learning and memory, hippocampal dendritic arbor, synaptic ultrastructure, and axonal myelin content in 9- and 11-month PSAPP mice, independent of reducing toxic amyloid deposits and astrogliosis. Our data indicate that SynCav1 gene therapy may be an option for AD and potentially in other forms of neurodegeneration of unknown etiology. The findings demonstrate that regardless of the etiology of the neuropathology, SynCav1 may be exploited to treat sporadic conditions or to be used in combination with already existing drugs or biologics designed to target known monogenic candidates linked to other neurodegenerative conditions (AD, ALS, MS).
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影响因子：
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作者：
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作者：
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DOI：
10.1073/pnas.1303646110
发表时间：
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影响因子：
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作者：
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