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

人类载脂蛋白 E 同工型在西尼罗河病毒暴露对阿尔茨海默病相关行为改变、认知损伤、神经炎症和神经病理学的长期影响中的作用

• 批准号: 10658408
• 负责人: ALEC J HIRSCH
• 金额: $ 23.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658408
• 关键词: 3' Untranslated Regions; Acceleration; Age; Age Months; Alleles; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Apolipoprotein E; Arctic mutation; Attenuated; Behavioral; Binding; Binding Proteins; Body Temperature; Brain; Capsid Proteins; Cells; Centenarian; Cerebrum; Chickenpox; Cholesterol Homeostasis; Circadian Rhythms; Cognitive; Communicable Diseases; DNA Methylation; Dengue Virus; Disease Progression; Dose; Episodic memory; Euthanasia; Exposure to; Flavivirus; Genes; Genetic; Genomics; HIV-1; Hepatitis C virus; Hepatitis E virus; Herpes zoster disease; Herpesvirus 1; Hippocampus; Homeostasis; Human; Human Amyloid Precursor Protein; Human Herpesvirus 4; Impaired cognition; Impairment; Infection; Inflammation; Inflammatory; Injury; Interferons; Interleukins; Klebsiella pneumoniae; Knock-in; Knock-in Mouse; Late Onset Alzheimer Disease; Learning; Lipids; Long-Term Effects; Macrophage; Malaria; Measures; Microglia; Mus; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Patients; Peptides; Performance; Pilot Projects; Plasma; Play; Predisposition; Presynaptic Terminals; Process; Production; Promoter Regions; Protein Isoforms; Purkinje Cells; Reporting; Risk; Risk Factors; Role; Senile Plaques; Stimulus; Synapses; Temperature; Testing; Time; Up-Regulation; Very low density lipoprotein; Viral Genome; Virus; Virus Diseases; Virus Inhibitors; West Nile viral infection; West Nile virus; Wild Type Mouse; age effect; age related neurodegeneration; amyloid peptide; apolipoprotein E-3; apolipoprotein E-4; behavioral phenotyping; chemokine; cognitive performance; cohort; cytokine; entorhinal cortex; glial activation; hippocampal atrophy; human model; improved; middle age; millimeter; mixed dementia; mouse model; nervous system disorder; neuroinflammation; neuron loss; neuropathology; neurotropic; new therapeutic target; novel; novel marker; novel therapeutic intervention; response; sensor; synuclein; targeted treatment; uptake; wireless

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.

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 海马体导致在阿尔茨海默病（AD）中看到的一些神经病理学和神经炎症。 存在三种人载脂蛋白E（E）同种型，其在胆固醇代谢中起作用：E2、E3和E4。 E4.与E3相比，E2对AD风险具有保护作用，而E4是AD风险因素。E4也与 人免疫缺陷病毒1（HIV-1）细胞进入和HIV-1疾病进展的增强。E 一个 易感性 水痘 是 HIV-1诱导的巨噬细胞中病毒产生和感染的抑制剂，参与发病机制和 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、EB病毒、疟疾（LM）和单核细胞增生李斯特菌肺炎克雷伯菌。在 单纯疱疹病毒1（HSV-1）的小鼠模型，潜伏的HSV-1基因组拷贝的大脑负荷， 与再激活风险相关，在E4小鼠中比E3小鼠高10倍。这些apoE亚型的差异可能 涉及极低密度脂蛋白（VLDL），因为E4比E3更好地与VLDL结合，并损害其脂肪分解 处理. WNV衣壳蛋白结合VLDL，就像登革病毒衣壳蛋白一样，并且被认为是重要的 用于病毒的摄取和运输。载脂蛋白E异构体与人淀粉样前体蛋白的差异性相互作用 APP及其产生的淀粉样肽A β 40和A β 42可能影响认知损伤 和神经退化APP、A β 40和A β 42可能在病毒感染中也很重要，AD患者可能 对病毒感染的易感性发生了改变我们将APP NL-G-F小鼠与靶向人apoE的小鼠杂交， 替代（TR）小鼠，并将这些小鼠用于所提出的研究。海马体显示神经病理学 在用减毒WNV毒株感染的WNV患者和C57 BL/6 J野生型小鼠的脑中， 与突触前末梢的白细胞介素34（IL-34）依赖性吞噬相关的学习障碍 在病毒感染期间和之后海马体中激活的小胶质细胞。我们将确定是否先前接触过 在6- 10岁儿童中，WNV hAPP/A β诱导的行为改变、认知障碍和神经病理学， 和12个月大的hAPP KI小鼠，以及这些效应是否是 与增强的神经炎症和小胶质细胞活化相关。我们包括新颖的无线温度 传感器分析体温和昼夜节律后，西尼罗河病毒暴露，并作为函数 hAPP/A β apoE同种型和年龄。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、神经元丢失以及APP和Aβ的上调不是AD和/或WNV感染的特异性。 虽然西尼罗河病毒和神经退行性变的发病机制之间有很大的重叠， 重要的是增加我们对相似性的理解，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。