胞外固有无结构区调控β淀粉样前体蛋白转运及加工的机制研究

The mal-processing of β-amyloid precursor protein not only impairs its normal function but leads to the accumulation of neurotoxic Aβ, which underlie the pathogenesis of Alzheimer’s disease. The processing of APP is controlled by its cellular traffic route. Despite that much is learned about how the cytoplasmic tail of APP contributes to its traffic and processing, little is known about the role of the extracellular portion, which accounts for over 85 % of the whole length of APP. Based on careful analysis of previous reports and the characteristics of APP family members, we hypothesize that the less conserved segments in the ectodomain of APP may play a critical role in the regulation of APP traffic and processing. Indeed, our preliminary results revealed that deletion of extracellular segments, in particular AcD, the intrinsic disordered region with low conservation, dramatically altered the traffic and processing of APP. The current project thus aims to comprehensively illustrate the molecular mechanism underlying the actions of APP extracellular domains and to provide new options for selective targeting of APP to treat Alzheimer’s disease.

β淀粉样前体蛋白（APP）加工异常所导致的功能失调及毒性分泌片段Aβ积累是阿尔茨海默症（AD）的主要病因。APP的加工方式高度依赖于其转运途径，但已有研究主要关注胞内区对APP转运、加工的调控，而对占APP全长85 %以上的胞外区在其中的作用却所知甚少。我们基于对前人发现及APP家族成员特征的仔细分析，推测APP胞外区中的低保守性结构域很可能在调控APP转运及加工中发挥重要作用。我们的前期工作显示，删除胞外区中的特定结构域（尤其是低保守性的固有无结构区AcD）对APP的转运及加工造成了极其显著的影响。本项目将在此基础上进一步阐明胞外区调控APP转运及加工的分子机制，以推进对APP加工调控及其如何行使功能或生成毒性产物的全面理解，同时也为以APP独有特征为标靶的AD干预策略提供新的思路。

β淀粉样前体蛋白（β-amyloid protein precursor, APP）的异常加工是阿尔茨海默症（Alzheimer’s disease, AD）的关键致病因素。本项目系统研究了APP的胞外区对加工的影响，发现固有无序区AcD结构域在其中扮演关键角色。虽然APP的加工与转运高度耦合，但AcD似乎并不影响转运，而是调节APP在脂筏膜微区内的富集。进一步的实验证据提示，AcD可能以分隔符的方式阻抑分子内互作，使APP处于可被分泌酶识别和加工的构象状态。此外，本项目还研究了APP胞外区对β淀粉样蛋白（β-amyloid peptide, Aβ）N端延长产物的产生的影响，提出了Aβ脱膜分泌的方式和机制，为理解和阻抑AD发生、发展过程提供了新的思路。