Role of human apolipoprotein E isoforms in long-term effects of West Nile Virus exposure on Alzheimer's disease-related behavioral alteration, cognitive injury, neuroinflammation, and neuropathology

项目摘要 西尼罗河病毒(WNV)可导致严重和持久的神经系统疾病。最初的感染是在 海马体导致了阿尔茨海默病(AD)中的一些神经病理和神经炎症。 人类载脂蛋白E(E)有三种亚型，它们在胆固醇代谢中起作用：E2、E3和 E4.与E3相比，E2对AD风险具有保护作用，而E4是AD风险因子。E4也与 随着人类免疫缺陷病毒1(HIV-1)进入细胞的增加和HIV-1疾病的进展。E 一个 敏感度 水痘 是 HIV-1诱导的巨噬细胞病毒产生和感染性的抑制物，参与了其发病机制和 其他传染病，包括单纯疱疹病毒-1、丙型肝炎病毒、戊型肝炎病毒、 带状疱疹病毒、爱泼斯坦-巴尔病毒、疟疾、肺炎克雷伯氏菌和单核细胞增生性李斯特氏菌。在……里面 一种单纯疱疹病毒1型(HSV-1)小鼠模型，脑内潜伏的HSV-1基因组拷贝，即 与重新激活风险相关的基因，在E4小鼠中是E3小鼠的10倍。这些载脂蛋白E亚型的差异可能 涉及极低密度脂蛋白(VLDL)，因为E4比E3与VLDL结合得更好，并损害其脂解作用 正在处理。西尼罗河病毒衣壳蛋白结合极低密度脂蛋白，登革病毒衣壳蛋白也是如此，被认为是重要的 用于病毒的摄取和运输。载脂蛋白E亚型与人淀粉样前体的差异性相互作用 蛋白(APP)和APP产生的淀粉样多肽A40和A42可能影响认知损伤 和神经退化。APP、A40和A42可能在病毒感染和AD患者中也很重要 对病毒感染的易感性发生了变化。我们将APP NL-G-F小鼠与人载脂蛋白E靶向杂交 替代(TR)小鼠，并将这些小鼠用于拟议的研究。海马体显示神经病理。 西尼罗河病毒患者和感染西尼罗河病毒弱毒株的C57BL/6J野生型小鼠的脑内呈现空间分布 依赖白介素34(IL-34)吞噬突触前终末相关的学习障碍 在病毒感染期间和感染后，激活了海马区的小胶质细胞。我们将确定之前的接触是否 TO-WNV加重HAPP/A-诱导的行为改变、认知障碍和神经病理 和12个月大的Happ Ki小鼠的载脂蛋白E异构体依赖的方式，以及这些影响是否 与增强的神经炎症和小胶质细胞激活有关。我们包括新的无线温度 传感器，用于分析西尼罗河病毒暴露后的体温和昼夜节律，并作为 HAPP/A载脂蛋白E亚型和年龄。我们还将评估血浆和脑中的细胞因子和趋化因子。 神经炎症、神经元丢失、APP和Aβ表达上调并非AD和/或西尼罗河病毒感染所特有。 虽然西尼罗河病毒和神经退行性变的发病机制有很大的重叠，但这一点还没有得到充分的研究。 重要的是增加我们对相似之处的理解，因为这将有助于识别 AD和其他神经退行性疾病的新生物标志物和治疗策略。这项建议是 根据PAR-22-094和NOT-AG-21-039提交。

Project Summary West Nile Virus (WNV) can cause severe and long-lasting neurological disease. Initial infection in the hippocampus results in some of the neuropathology and neuroinflammation seen in Alzheimer's disease (AD). There are three human apolipoprotein E (E) isoforms, which play a role in cholesterol metabolism: E2, E3, and E4. Compared to E3, E2 is protective with regard to AD risk, while E4 is an AD risk factor. E4 is also associated with enhanced entry of human immunodeficiency virus 1 (HIV-1) cell entry and HIV-1 disease progression. E an susceptibility varicella is HIV-1-inducible inhibitor of viral production and infectivity in macrophages, involved i n the pathogenesis and to other infectious diseases, including herpes simplex virus-1, hepatitis C virus, hepatitis E virus, zoster virus, Epstein-Barr virus, malaria, (LM), andListeria monocytogenes Klebsiella pneumoniae. In a mouse model of herpes simplex virus 1 (HSV-1), the cerebral load of latent HSV-1 genomic copies, which is associated with the reactivation risk, is 10-fold higher in E4 than E3 mice. These apoE isoform differences might involve very low-density lipoproteins (VLDL), as E4 binds better than E3 to VLDL and impairs their lipolytic processing. WNV capsid protein binds VLDL, as does Dengue virus capsid protein and is thought to be important for uptake and transport of virus. The differential interactions of apoE isoforms with human amyloid precursor protein (APP) and with the amyloid peptides A40 and A42 generated from APP might influence cognitive injury and neurodegeneration. APP, A40 and A42 might be important in viral infections as well and AD patients might have an altered susceptibility to viral infections. We crossed APP NL-G-F mice with human apoE targeted replacement (TR) mice and will use these mice for the proposed study. The hippocampus shows neuropathology in brains of WNV patients and C57BL/6J wild-type mice infected with an attenuated WNV strain show spatial learning impairments associated with interleukin 34 (IL-34)-dependent engulfment of presynaptic terminals by activated microglia in the hippocampus during and after viral infection. We will determine whether prior exposure to WNV worsens hAPP/A-induced behavioral alterations and cognitive impairments and neuropathology in 6- and 12-month-old hAPP KI mice in an apoE isoform-dependent fashion, and whether these effects are associated with enhanced neuroinflammation and microglial activation. We include novel wireless temperature sensors to analyze body temperature and circadian rhythms following WNV exposure and as a function of hAPP/A apoE isoform, and age. We will also assess cytokines and chemokines in plasma and brain. Neuroinflammation, neuron loss and upregulation of APP and Aβ are not specific to AD and/or WNV infection. While there is significant overlap between WNV and neurodegeneration pathogenesis, this has been understudied and it is important to increase our understanding about the similarities as this will facilitate the identification of novel biomarkers and therapeutic strategies for AD and other neurodegenerative disorders. This proposal is submitted in response to PAR-22-094 and NOT-AG-21-039.