硫酸乙酰肝素调控β-分泌酶表达的作用机制研究

阿尔茨海默症(AD)是一种中枢神经系统退行性疾病，目前致病机理尚未阐明，而且缺乏有效的治疗手段。研究表明Aβ水平失衡和寡聚化是引发AD的中心环节。因此，减少Aβ生成是治疗AD的关键。β-分泌酶（BACE1）是Aβ生成的限速酶，其调控失常是AD发病的重要因素之一，然而BACE1的生理调控机制尚未完全阐明。硫酸乙酰肝素(HS)可与BACE1相互结合,但其对BACE1的调控作用尚不明确。我们的预实验结果表明，下调AD转基因鼠原代神经元细胞中HS糖链水平可以降低BACE1表达和Aβ生成，这一发现揭示了一个新的BACE1调控途径。本项目拟在前期研究的基础上深入探讨HS糖链调控BACE1表达的具体机制，阐明HS糖链精细结构对BACE1表达和Aβ分泌的影响。本项目的研究对阐明BACE1的生理调控机制和AD的发病机理，以及完善HS糖链的生物学功能均有重要意义，并为研发AD治疗药物奠定了重要理论基础。

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly. The cause of AD is still poorly understood and currently there are no treatments can stop or reverse the progression of the disease. Studies show that overproduction and oligomerization of Aβ in the brain is the major cause of AD, and the key question in the field now is how to lower the production of Aβ. BACE1, an enzyme that initiates APP processing to generate toxic Aβ, plays a crucial part in AD pathogenesis. However, the regulation mechanisms of BACE1 are not completely understood. Heparan sulfate (HS) can directly interact with BACE1, but the functional consequence of this interaction is still unknown. Our pilot studies indicate that deletion of endogenous HS with specific drug or enzyme in primary cortical cells from APP transgenic mice reduces the level of BACE1 and attenuates Aβ secretion. This project will further investigate the precise mechanism underlying the reduction of BACE1 expression caused by removal of HS, and also examine the functions of different HS fine structures in regulation of BACE1 expression and Aβ production. Our study will uncover a new physiological function of HS, leading to a better understanding of BACE1 regulation mechanism and the cause of AD, and also provide new clues for development of AD therapeutics.