Grb10对AD相关的认知功能障碍和神经病理变化的影响及其机制研究

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by memory loss and cognitive impairment. Its neuropathological features include extracellular accumulations of amyloid-β peptides in the form of plaques and intracellular tangles, consisting of hyperphosphorylated tau proteins. The etiology and pathogenic mechanisms resulting in AD remain unknown. We found that Grb10, a negative regulator of insulin/IGF-1 signaling, is highly expressed in brain regions involved in learning and memory and its expression in the brain increases with age. Moreover, preliminary studies suggest that brain Grb10 affects cognitive function and the activity of β-secretase (BACE1), a key enzyme in amyloidogenesis. This study will use mouse models with either Grb10 overexpression or deletion in the brain in combination with triple transgenic AD (3xTg-AD ) mouse model to explore the effects of Grb10 on cognitive function and neruopathologies relevant to AD. These studies will provide insights into molecular pathogenic mechanisms and possible novel treatment strategies of AD.

阿尔茨海默病(Alzheimer's disease , AD)是一种中枢神经系统退行性疾病,神经行为改变主要表现为学习记忆功能障碍及进行性痴呆，其病理特征包括细胞外大量β-淀粉样蛋白 (β- amyloid,Aβ)沉积形成老年斑和在神经元内Tau蛋白的磷酸化形成神经纤维缠结。目前AD确切的发病机制仍不清楚。我们发现胰岛素和IGF-1信号的负向调节因子Grb10在学习记忆相关脑区高量表达，且随年龄增长而表达增加。初步实验结果表明脑源性Grb10对认知功能和Aβ产生过程中的关键限速酶---β-分泌酶（BACE1）的活性有调节作用。本项目将利用脑特异性Grb10基因敲除和过表达小鼠结合三重转基因AD小鼠(3xTg-AD)模型，研究Grb10对AD认知功能、神经病理变化的影响和作用机制。进一步阐明与AD相关的认知障碍和神经病理发生机制，并有望为AD提供新的治疗策略和理论基础。