3-羟基丁酸甲酯对tau病理诱导的阿尔茨海默症治疗效果及潜在机制研究

Alzheimer’s disease (AD) is a common degenerative disease of the central nervous system. The most remarkable pathological hallmarks are β-amyloid (Aβ) plaques and neurofibrillary tangles (NFT). The current clinical drugs have no obvious effect, so need to develope more effective drug for AD treatment. The previous study of applicant showed that 3-hydroxybutyratemethyl ester (HBME) could effectively improve the spatial learning and memory ability of APP/PS1 double transgenic mice (an AD model mice induced by Aβ pathology), reduce amyloid-β deposition and inhibit the atrophy of hippocampus in AD mouse brain (Zhang JY, et al. Biomaterials, 2013). Multiple lines of research all emphasize the role of tau as a downstream mediator of Aβ-triggered dementia. So we speculate that the therapeutic effect of HBME on AD may through the tauopathy. This project will detect the effect of HBME on the expression level of hyperphosphorylated tau and the synaptic function damage induced by pathological change of tau, which may reveal the underlying mechanisms of HBME on tauopathies. In addition, we will study the effect of HBME on the learning and memory ability of P301S mutant human tau transgenic mice (an AD model mice induced by tauopathies), as well as the brain atrophy, which will provide more comprehensive theoretical basis and experimental evidence for developing HBME as an anti-AD drug.

阿尔茨海默症（AD）是常见的神经退行性疾病，其显著病理特征包括β-淀粉样斑（Aβ）及神经纤维缠结。目前的临床药物无明显治疗效果，亟需研发出更有效的抗AD药物。申请人前期研究发现3-羟基丁酸甲酯（HBME）能有效提升APP/PS1双转基因小鼠（Aβ病理AD模型小鼠）空间学习记忆能力，抑制脑内Aβ沉积及脑萎缩的发生（Zhang JY, et al. Biomaterials, 2013）。研究表明，Aβ引发AD的起始，而后很多功能损伤则是由tau蛋白介导。故我们推测HBME很可能通过tau蛋白病理通路来达到治疗AD的效果。本课题将检测HBME对tau蛋白过度磷酸化及tau病变引起的突触功能损伤的影响，以揭示其对tau蛋白病理通路的作用机制；并研究HBME对P301S htau转基因小鼠（tau病理AD模型小鼠）脑萎缩以及学习记忆能力的影响，为将其开发成抗AD药物提供更全面的理论基础和实验依据。

阿尔茨海默症（AD）是常见的神经退行性疾病，其显著病理特征包括β-淀粉样斑（Aβ）及神经纤维缠结（NFT）。目前的临床药物无明显治疗效果，亟需研发出更有效的抗AD药物。申请人前期研究发现3-羟基丁酸甲酯（HBME）能有效提升APP/PS1双转基因小鼠（Aβ病理AD模型小鼠）空间学习记忆能力，抑制脑内Aβ沉积及脑萎缩的发生（Zhang JY, et al. Biomaterials, 2013）。研究表明，Aβ引发AD的起始，而后很多功能损伤则是由tau蛋白介导。本课题欲进一步探究HBME是否能对抗tau蛋白病理以达到治疗AD的效果。通过构建AD细胞模型，检测HBME对tau蛋白过度磷酸化及tau病变引起的突触功能损伤的影响，从细胞、分子层面揭示其对tau蛋白病理通路的可能作用机制。结果显示，在小鼠神经瘤细胞系N2A中，HBME可以有效对抗由多种特异性抑制剂引起的tau病理过程，提升细胞存活率、抑制tau蛋白过度磷酸化并改善突触功能，而其作用机制是通过影响PP2A、GSK-3β通路来达到的。本研究为将HBME开发成抗AD药物提供了进一步的理论基础和实验依据。