循环胆固醇及其相关基因变异在早发型阿尔茨海默病中的作用及机制

The role of circulating cholesterol and its related gene mutations in early-onset Alzheimer's disease and its mechanism

摘要:

早发型阿尔茨海默病（EOAD）是65岁之前发病的以进行性认知障碍及行为异常为特征的神经系统退行性疾病。作为常染色体显性遗传疾病，EOAD的发病机制主要与基因突变有关。研究表明胆固醇及其相关基因变异参与EOAD发病。胆固醇可能通过载脂蛋白E基因ε4等位基因（ApoE ε4）介导促进EOAD发生，也可能是EOAD独立于ApoE ε4的危险因素，具体作用机制尚不明确。对EOAD患者进行基因检测发现，与胆固醇代谢相关的载脂蛋白A1（ApoA1）基因、载脂蛋白B（ApoB）基因、载脂蛋白C1（ApoC1）基因、载脂蛋白C2（ApoC2）基因、载脂蛋白D（ApoD）基因、载脂蛋白E（ApoE）基因、三磷酸腺苷结合盒A1转运蛋白（ABCA1）基因、三磷酸腺苷结合盒A2转运蛋白（ABCA2）基因、三磷酸腺苷结合盒A7转运蛋白（ABCA7）基因、3-羟基-3-甲基戊二酸单酰辅酶A还原酶（HMGCR）基因、分拣蛋白相关受体1（SORLl）均与EOAD有关。现将胆固醇及相关基因变异在EOAD发病机制中的作用做一综述，旨在为EOAD早期诊断提供临床思路，为EOAD的治疗提供新的靶点。

Abstract:

Early-onset Alzheimer's disease (EOAD) is a neurodegenerative disease characterized by progressive cognitive impairment and behavioral abnormalities. The disease develops before the age of 65. EOAD, as an autosomal dominant genetic disease, has a pathogenesis mainly related to gene mutations. Studies have shown that cholesterol and its related gene mutations are involved in the pathogenesis of EOAD. Cholesterol may promote the development of EOAD through the mediation of apolipoprotein E ε4 allele (ApoE ε4), or it may be a risk factor for EOAD independent of ApoE ε4, the mechanism of which remains unclear. Genetic tests in patients with EOAD found that all of the following genes associated with the metabolism of cholesterol were related to the development of EOAD:apolipoprotein A1 (ApoA1) gene, apolipoprotein B (ApoB) gene, apolipoprotein C1 (ApoC1) gene, apolipoprotein C2 (ApoC2) gene, apolipoprotein D (ApoD) gene, apolipoprotein E (ApoE) gene, ATP-binding cassette transporter A1 (ABCA1) gene, ATP-binding cassette transporter A2 (ABCA2) gene, ATP-binding cassette transporter A7 (ABCA7) gene, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) gene, and sortilin-related receptor 1 (SORL1) gene. This review summarizes the role of cholesterol and its related gene mutations in the pathogenesis of EOAD, aiming to shed clinical light on early diagnosis of EOAD and to provide a new target for the treatment of EOAD.