细胞周期负性调控因子TOB在早期阿尔茨海默病发病中作用机制研究

Alzheimer disease (AD) is one of the most common neurodegenerative diseases in the elderly. For being no clear etiology or pathogenesis, there was no effective drugs or means about treatment. The main pathological changes of the brain in AD patients: the large number of nerve cells in the formation of abnormal phosphorylation of microtubule-associated protein tau protein as the main component of neurofibrillary tangles, as well as a large number of cells between the deposition of beta-amyloid peptide Aβ components of senile plaques. Privious study find that cell cycle abnormalities may be associated with this pathological change. Cell cycle regulators cyclin D1 involves in AD early phosphorylation of tau and Aβ abnormal accumulation. In peripheral tissues, TOB is an important regulator on the upstream of cyclin D1. On the contrary, whether the TOB protein involve in the regulation of cyclin D1 and how to adjust, is not clear. By using animal behavior, pharmacological intervention and molecular biology methods,we attempte to explore the expression of TOB and its downstream regulators cyclin D1 in the abnormal activation of the cell cycle in animal models for Alzheimer's disease (progeria mice SAMP8) and normal mouse. Hoping to provide targets of early intervention and the choice of drug prevention and treatment in AD.

阿尔茨海默病(AD) 是老年人中最常见的神经退行性疾病，其病因和发病机制不清，治疗尚没有明确有效的药物和手段。AD患者脑内的主要病理变化是：神经细胞内大量形成以异常磷酸化的微管相关蛋白tau蛋白为主要成分的神经原纤维缠结，以及细胞间沉积大量以β- 淀粉样多肽Aβ为核心成分的老年斑。研究发现，细胞周期异常可能与这种病理变化相关，细胞周期蛋白cyclin D1参与了AD早期磷酸化tau蛋白和Aβ异常积聚。在外周组织，TOB是cyclin D1上游的一个重要调节因子，在中枢神经，TOB蛋白是否也参与了对cyclin D1的调节及如何调节，目前尚不清楚。因此，本研究试图通过对阿尔茨海默病模型（快速老化型小鼠SAMP8）及正常小鼠采用行为学、药物干预及分子生物学检测病理变化等方法，探索TOB及其下游相关蛋白cyclin D1在细胞周期异常激活中的作用，为AD的早期干预和选择药物防治靶点提供理论依据。

阿尔茨海默病(AD) 是老年人中最常见的神经退行性疾病，其病因和发病机制不清，治疗尚没有明确有效的药物和手段。我们探索了TOB蛋白信号通路在阿尔茨海默病中的作用以及BDNF组蛋白H3乙酰化表观遗传学修饰水平在阿尔茨海默病中的作用，发展了应用二甲双胍逆转的阿尔茨海默病诱导的记忆损伤。同时我们还发现在前边缘皮质过表达蛋白激酶Mζ能够增强长时程记忆的形成，从而为阿尔茨海默病的治疗提供了新的靶点。另外，我们还探索了应激诱导的记忆损伤，发现NPAS4在应激诱导的消退记忆障碍中发挥重要作用，我们还发现杏仁核不同神经元集群在应激诱导的情感障碍中的作用。