阿尔兹海默病（AD）是一类常见的神经退行性疾病，以脑内出现淀粉样蛋白（Aβ)聚合物和后期大量神经元凋亡为主要形态学特征。一般认为脑内Aβ的聚集导致的神经毒性是AD病发的诱因，但在AD早期Aβ前体蛋白（APP）如何被选择性剪切生成更多具有神经毒性的Aβ42以及胞内段（AICD）信号转导异常与AD的关联仍未知。本项目以此科学问题为切入点，探索APP被不同分泌酶剪切调控机制，聚焦Aβ片段对蛋白酶剪切APP的逆向调控及胞内产物AICD的信号转导机制。APP除了通过剪切生成Aβ片段导致神经毒性外，研究提示AICD信号转导异常与AD也密切相关。综合我们前期结果，本项目聚焦AICD信号转导与胞内钙离子平衡之间的关联，重点关注内质网、线粒体上IP3R等钙离子通道等。考虑到以往针对Aβ以及相关分泌酶靶向药物研发的困境，本项目除了对与AD相关的病理等基础研究有积极推作用，或为AD药物研发提供新方向。

Alzheimer's disease (AD) is a common type of neurodegenerative disease characterized by the appearance of amyloid (β-amyloid, Aβ) aggregates and a large number of neuronal loss in the brain. It is generally believed that the neurotoxicity caused by the aggregation of Aβ peptides (especially Aβ42) in the brain is the main cause of AD, but how the β-amyloid precursor protein (APP) is selectively cleaved with releasing more neurotoxic Aβ42 in early AD, and the association of abnormal APP intracellular domain (AICD) signal transduction with AD are not clear. Taking the scientific problems as the starting point, this project explores the mechanisms of sequential and selective proteolytic cleavage of APP by different secretases, focusing on the reverse regulation of APP cleavage by Aβ fragments. We planned to launch from the perspectives of molecular structure interaction and the influence on the pathological process of AD. In addition to the neurotoxicity caused by Aβ fragments generated from APP, studies indicates that abnormal AICD signal transduction is closely related to AD. Based on our previous studies, this project will focus on the association between AICD signal transduction and intracellular Ca2+ ion balance, focusing on the functions of Ca2+ channels such as IP3R in the endoplasmic reticulum and mitochondria. Considering the previous difficulties in the research and development of targeted drugs for Aβ and related secretases, this project will not only positively promote the pathologic and basic research related to AD, but also provide new directions for the research and development of drugs for AD.