载脂蛋白E
腺相关病毒
疾病
遗传增强
等位基因
医学
载体(分子生物学)
基因传递
淀粉样蛋白(真菌学)
阿尔茨海默病
淀粉样前体蛋白
病理
免疫学
生物
神经科学
基因
遗传学
重组DNA
作者
Lingzhi Zhao,Andrew J. Gottesdiener,Mayur Parmar,Mingjie Li,Stephen M. Kaminsky,Marı́a J. Chiuchiolo,Dolan Sondhi,Patrick M. Sullivan,David M. Holtzman,Ronald G. Crystal,Steven M. Paul
标识
DOI:10.1016/j.neurobiolaging.2016.04.020
摘要
The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-β (Aβ) peptide deposition and amyloid burden (ε4 > ε3 > ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)–mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aβ levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aβ burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aβ and amyloid deposition. We further demonstrate that a widespread reduction of brain Aβ burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease.
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