骨形态发生蛋白在Aβ毒性病变中稳定神经突起内骨架系统的机制研究

Alzheimer's disease (AD) is a senile disease which has high morbidity and high social burden, and there is still not effective treatment. Impaired skeleton system in neurite caused by amyloid β (Aβ) deposition is an important pathological feature of AD. Our preliminary experiments in vitro demonstrated that bone morphogenetic protein (BMP) can protect neurons against Aβneurotoxicity and maintain the stabilization of neurite skeleton. The protective mechanism and protective effect in vivo of BMP are needed to clarify urgently. The applicant hypothesizes: the mechanism of BMP protecting the stabilization of cytoskeleton in neurite is LIM kinase 1(LIMK1)- dependent. We will adopt AD animal models and Aβ damage cell models interfered with BMP and/or LIMK1 inhibitor (S3 peptide) as research objects, to analyse the stabilization of skeleton system in neurite and specific change of the upstream regulatory molecules for further revealing the mechanism of BMP protecting neurite. We will evaluate the change of cognitive behavior and pathomorphology for validating the protective effect of BMP in vivo. We wish the research can provide new ideas for discovering potential targets for clinical drug therapy.

阿尔茨海默病（AD）是一种高致残率、高社会负担的老年疾病，目前仍缺乏有效治疗手段。β淀粉蛋白（Aβ）沉积导致神经突起内骨架系统受损是AD的重要病理特征之一。申请人前期实验发现骨形态发生蛋白（BMP）在Aβ损伤细胞模型中具有神经保护作用，能够稳定神经突起内骨架系统，其保护机制和体内应用效果亟待阐明。本研究提出机制假说：BMP在Aβ毒性病变中通过LIM激酶1（LIMK1）途径来稳定神经突起内骨架系统。我们拟采用BMP与LIMK1抑制剂（S3肽）干预的AD小鼠模型和Aβ损伤细胞模型，分析LIMK1对BMP稳定神经突起内骨架系统的影响及其上游调节通路的特异性变化，以期阐明相应分子机制；并评价BMP对AD小鼠认知行为学和神经病理学的影响，进一步在体验证BMP的神经突起保护作用，为发现AD临床药物治疗的潜在靶点提供新思路。