Intracerebral Expression of AAV-APOE4 Is Not Sufficient to Alter Tau Burden in Two Distinct Models of Tauopathy
Intracerebral Expression of AAV-APOE4 Is Not Sufficient to Alter Tau Burden in Two Distinct Models of Tauopathy
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DOI：
10.1007/s12035-019-01859-4
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发表时间：
2020-04-01
影响因子：
5.1
通讯作者：
Chakrabarty, Paramita
中科院分区：
文献类型：
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作者：
Koller, Emily J.;De la Cruz, Elsa Gonzalez;Chakrabarty, Paramita
载脂蛋白E4 （APOE4）是散发性阿尔茨海默病（AD）的主要遗传危险因素，其特征是淀粉样蛋白斑块和tau缠结。虽然APOE4在A β发病机制中的作用已经在啮齿动物模型中得到了机制上的定义，但APOE4与tau发病机制的关系尚不清楚。最近的研究表明，APOE亚型依赖性改变在tau病理和神经变性之间可能存在相关性。为了探究APOE4的神经元表达是否会引发牛头病，我们在两种不同的牛头病模型——rtg4510和PS19系中传递了表达人类APOE4的腺相关病毒（AAV）。新生儿rTg4510和PS19小鼠脑室内递送AAV-APOE4导致神经元中APOE4蛋白增加，但未导致磷酸化tau负荷、缠结前tau病理或银阳性缠结病理的改变。突触蛋白的生化分析未发现实质性的改变。我们的研究结果表明，使用aav介导的方法，APOE4在神经元中的过度表达不足以加速或以其他方式改变在过度表达突变的人类tau的小鼠中发生的固有tau病理。
Apolipoprotein E4 (APOE4) is the major genetic risk factor for sporadic Alzheimer's disease (AD), which is characterized by amyloid beta (A beta) plaques and tau tangles. Though the role of APOE4 in A beta pathogenesis has been mechanistically defined in rodent models, much less is known regarding the relationship of APOE4 to tau pathogenesis. Recent studies have indicated a possible correlation between APOE isoform-dependent alterations in tau pathology and neurodegeneration. To explore whether neuronal expression of APOE4 triggers tauopathy, here we delivered adeno-associated viruses (AAV) expressing human APOE4 in two different models of tauopathy-rTg4510 and PS19 lines. Intracerebroventricular delivery of AAV-APOE4 in neonatal rTg4510 and PS19 mice resulted in increased APOE4 protein in neurons but did not result in altered phosphorylated tau burden, pretangle tau pathology, or silver-positive tangle pathology. Biochemical analysis of synaptic proteins did not reveal substantial alterations. Our results indicate that over-expression of APOE4 in neurons, using an AAV-mediated approache, is not sufficient to accelerate or otherwise alter the inherent tau pathology that occurs in mice overexpressing mutant human tau.