Department of Neuroscience, University of Florida, Gainesville, FL, 32610, USA.
Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA.
Mol Neurobiol. 2020 Apr;57(4):1986-2001. doi: 10.1007/s12035-019-01859-4. Epub 2020 Jan 6.
Apolipoprotein E4 (APOE4) is the major genetic risk factor for sporadic Alzheimer's disease (AD), which is characterized by amyloid β (Aβ) plaques and tau tangles. Though the role of APOE4 in Aβ 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.
载脂蛋白 E4（APOE4）是散发性阿尔茨海默病（AD）的主要遗传风险因素，其特征是淀粉样β（Aβ）斑块和tau 缠结。尽管 APOE4 在啮齿动物模型中的 Aβ发病机制中的作用已在机制上得到定义，但对于 APOE4 与 tau 发病机制的关系知之甚少。最近的研究表明，tau 病理学和神经退行性变中 APOE 同工型依赖性改变之间可能存在相关性。为了探讨神经元表达 APOE4 是否引发 tau 病，我们在这里使用两种不同的 tau 病模型（rTg4510 和 PS19 系），递送表达人 APOE4 的腺相关病毒（AAV）。在新生 rTg4510 和 PS19 小鼠的侧脑室中递送 AAV-APOE4 导致神经元中 APOE4 蛋白增加，但不会导致磷酸化 tau 负担、前缠结 tau 病理学或银阳性缠结病理学改变。突触蛋白的生化分析并未显示出实质性改变。我们的结果表明，使用 AAV 介导的方法在神经元中过表达 APOE4 不足以加速或以其他方式改变过度表达突变型人 tau 的小鼠中发生的固有 tau 病理学。
