ApoE4转基因小鼠在阿尔茨海默病研究中的应用进展

Progress in application of Apo E4 transgenic mice in research into Alzheimer’s disease

载脂蛋白E(apolipoprotein E,ApoE)在脑中参与胆固醇和脂质代谢,将胆固醇输送到神经元,并清除脂质碎片以促进髓鞘修复。ApoE4是ApoE三种亚型之一,为散发型阿尔茨海默病(sporadic Alzheimer’s disease,SAD)最主要的遗传危险因素。其发病机制可能涉及增加脑内β-淀粉样蛋白(β-amyloid,Aβ)沉积并减少其清除率、Tau蛋白过度磷酸化、脂质代谢异常和血脑屏障损伤。ApoE4转基因小鼠最早在2~4月龄出现Aβ相关病理表型,4月龄时海马总Tau蛋白和磷酸化Tau蛋白含量增加,且发生神经元丢失、树突损坏及突触减少,9月龄空间学习记忆能力下降。ApoE4转基因小鼠广泛用于AD防治药物的研究,如胆碱酯酶抑制剂利斯的明、谷氨酰胺酶拮抗剂JHU-083、GABA能神经元受体增强剂戊巴比妥、改善脑血管功能障碍的表皮生长因子、二十二碳六烯酸、菊粉和姜黄素等。本综述可为ApoE4转基因小鼠在AD研究中的应用提供参考与借鉴作用。

The apolipoprotein E(ApoE)is involved in cholesterol and lipid metabolism in the brain,transporting cholesterol to neurons and removing lipid debris to facilitate myelin repair.ApoE4,one of three subtypes of ApoE,is the most important genetic risk factor for sporadic Alzheimer’s disease(AD).ApoE4 increases the deposition and reduces the clearance rate of Aβ,enhances hyperphosphorylation of Tau protein,induces abnormal lipid metabolism in the brain,and impairs the brain and blood-brain barrier.ApoE4 transgenic mice were used to study AD pathogenesis and prevention.ApoE4 transgenic mice showed decreased abilities in spatial learning and memory at the age of 9 months and a pathological phenotype related toβ-amyloid at 2~4 months.At 4 months,total Tau and phosphorylated Tau levels increased,and a loss of neurons and damage to dendrites and synapses occurred in the hippocampus.ApoE4 transgenic mice have been used to study the prevention and treatment of AD drugs such as the GABA neuronal receptor agonist pentobarbital,the glutamine antagonist JHU-083,epidermal growth factor,inulin,and curcumin.This review provides a reference for those applying ApoE4 transgenic mice in AD research.