PS1基因F105C突变在家族性阿尔茨海默病发病中的作用机制研究

Alzheimer's disease pathogenesis is complex, has not been fully clarified. Early old protein (PS1) gene mutation is mainly reason for familial AD (FAD). we found a Chinese FAD ，genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Function prediction analysis of this mutation existed in functional areas, can be significant changes protein function, and has pathogenic significance. This project intends to build adenovirus vector with mutant PS1 (F105C), transfect respectively human neuroblastoma SHSY5Y cells, and the original generation of hippocampal neuron, detecting neuronal γ-secretase expression，activity and Aβlevel.Comparing the Aβ,PS1 in blood, cerebrospinal fluid,blood cells between family mutation carriers and noncarriers, explore the influence for mutant PS1 (F105C)on Aβmetabolism,PS1 (F105C) mutation expression,γ- secretase activity. Furthermore,preparation of PS1 (F105C) transgenic mice model of mutation, from the wayγ- secretase depend on or not rely on , explore the role and mechanism for PS1 (F105C) mutation on the pathogenesis of alzheimer's disease.

阿尔茨海默病（Alzheimer’s disease，AD）发病机制复杂，尚未完全阐明。早老素蛋白（PS1）基因突变是导致家族性AD（FAD）主要原因。我们发现一个中国人FAD家系，家系AD患者PS1基因第四外显子105号密码子发生TTT→TGT错意突变,导致该位点由原来苯丙氨酸变为半胱氨酸，功能预测分析此突变位于功能区，可显著改变蛋白功能，具有致病意义。本项目拟构建突变型PS1（F105C）腺病毒载体，分别转染人神经母细胞瘤SH-SY5Y细胞、原代海马神经元，检测神经元γ-分泌酶表达、活性和Aβ水平；比较该家系突变携带者与非携带者血液、脑脊液、血细胞PS1、Aβ水平和γ-分泌酶活性，探讨PS1（F105C）突变对PS1表达、γ-分泌酶活性、Aβ代谢的影响；进一步制备人PS1（F105C）突变的转基因小鼠模型，从γ-分泌酶依赖途径和非依赖途径，探讨该突变在阿尔茨海默病发病中的作用