阿尔茨海默病和骨质疏松是最常见的老年疾病。骨代谢和中枢神经系统有密切联系。寻找来自于骨并能调节神经系统，尤其是神经变性疾病进展的分子和/或信号通路是目前最前沿的研究核心。自噬功能异常是阿尔茨海默病发病过程中的一个重要改变。成骨细胞来源的骨钙素（osteocalcin，OCN）对全身各脏器都有广泛作用，如参与能量代谢和生殖功能的调节，同时可能还参与记忆认知功能的调控。mTORC1信号是调节自噬的一个重要通路，在阿尔茨海默病发生发展中起重要调控作用。本课题将利用成骨细胞特异性OCN敲除小鼠和阿尔茨海默病转基因小鼠模型，在额叶，海马神经元和骨组织几个层面，全面研究OCN通过mTORC1信号途径调节自噬功能，从而调控阿尔茨海默病发病过程的具体分子机制。本研究将扩大骨生理学的内涵，为探讨以骨骼调控老年性神经变性疾病提供新的思路，为寻找阿尔茨海默病新的治疗靶标和研发新型治疗药物提供坚实的理论依据。

Alzheimer's disease (AD) and osteoporosis are the most common age-related diseases. Our previous works pointed to a deep correlation between bone homeostasis and central nervous system. Bone is now widely accepted as an endocrine organ, however, the precise mechanism for the modulatory effect of bone on AD is still rarely reported. Autophagy dysfunction is a main pathophysiological abnormality in AD. Osteoblast-derived osteocalcin (OCN) has diverse effects on whole body metabolism, such as the regulation of energy metabolism and gonadal function, and is also involved in regulating the function of the central nervous system，while mTORC1 signaling plays a vital role in regulating autophagy and the progression of AD. With the use of OCN deficient and transgenic AD mouse models, we are able to investigate the roles of OCN/mTORC1 signaling pathway in AD, and explore its mechanism in frontal lobe, hippocampus, neurons and bone. This project may help to expand the scope of skeleton physiology, shed light on the novel ways in modulating neurodegenerative diseases by manipulating skeleton, and narrow down the intervention targets. It will definitely provide solid evidence and rational to develop brand-new therapeutic agents for AD.