Dl-3-n-Butylphthalide Reduces Cognitive Deficits and Alleviates Neuropathology in P301S Tau Transgenic Mice.
Dl-3-n-Butylphthalide Reduces Cognitive Deficits and Alleviates Neuropathology in P301S Tau Transgenic Mice.
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DOI：
10.3389/fnins.2021.620176
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发表时间：
2021
影响因子：
4.3
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Chang Y;Yao Y;Ma R;Wang Z;Hu J;Wu Y;Jiang X;Li L;Li G
阿尔茨海默病（AD）是一种破坏性和负担性的神经退行性疾病，其最常见的特征之一是由异常tau蛋白组成的神经原纤维缠结（nft）。动物实验表明dl-3-正丁基酞（dl-NBP）可减轻APP/PS1和SAMP8小鼠模型的认知功能障碍。然而，与此相关的潜在机制尚不清楚。在本研究中，我们检测了dl-NBP对P301S转基因小鼠学习和记忆的影响，P301S转基因小鼠携带P301S突变的人tau基因。我们发现，与P301S小鼠相比，补充dl-NBP可有效改善P301S tau转基因小鼠的行为缺陷并挽救突触丧失。此外，我们还发现它能显著抑制Ser262位点的过度磷酸化tau蛋白，并降低与Ser262位点tau蛋白相关的MARK4的活性。最后，dl-NBP治疗在P301S小鼠中具有抗炎作用并降低炎症反应。总之，我们的研究结果提供了证据，证明dl-NBP在治疗包括AD在内的牛头病变方面具有很好的潜力。
Alzheimer’s disease (AD) is a destructive and burdensome neurodegenerative disease, one of the most common characteristics of which are neurofibrillary tangles (NFTs) that are composed of abnormal tau protein. Animal studies have suggested that dl-3-n-butylphthalide (dl-NBP) alleviates cognitive impairment in mouse models of APP/PS1 and SAMP8. However, the underlying mechanisms related to this remain unclear. In this study, we examined the effects of dl-NBP on learning and memory in P301S transgenic mice, which carry the human tau gene with the P301S mutation. We found that dl-NBP supplementation effectively improved behavioral deficits and rescued synaptic loss in P301S tau transgenic mice, compared with vehicle-treated P301S mice. Furthermore, we also found that it markedly inhibited the hyperphosphorylated tau at the Ser262 site and decreased the activity of MARK4, which was associated with tau at the Ser262 site. Finally, dl-NBP treatment exerted anti-inflammatory effects and reduced inflammatory responses in P301S mice. In conclusion, our results provide evidence that dl-NBP has a promising potential for the therapy of tauopathies, including AD.
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