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）会引起严重和持久的神经系统疾病。最初感染 海马导致在阿尔茨海默氏病（AD）中看到的一些神经病理学和神经炎症。 有三种人载脂蛋白E（E）同工型在胆固醇代谢中发挥作用：E2，E3和 E4。与E3相比，E2在AD风险方面受到保护，而E4是AD风险因素。 E4也关联 随着人类免疫缺陷病毒1（HIV-1）细胞进入和HIV-1疾病进展的加强。 e 一个 敏感性 水痘 是 HIV-1可诱导的巨噬细胞病毒生产和感染的抑制剂，参与发病机理和 对于其他传染病，包括单纯疱疹病毒1，丙型肝炎病毒，丙型肝炎病毒， 带状疱疹病毒，爱泼斯坦 - 巴尔病毒，疟疾（LM）和单核细胞增生李斯特氏菌肺炎。在 单纯疱疹病毒1（HSV-1）的小鼠模型，潜在的HSV-1基因组拷贝的大脑负荷，这是 与重新激活风险相关，E4中的E3小鼠高10倍。这些APOE同工型可能 涉及非常低密度的脂蛋白（VLDL），因为E4的结合比E3与VLDL更好并损害其脂肪溶解 加工。 wnv capsid蛋白和登革热病毒capsid蛋白也结合了VLDL，被认为很重要 用于摄取和传输病毒。 ApoE同工型与人淀粉样前体的差异相互作用 蛋白质（APP）以及由APP产生的淀粉样蛋白A40和A42可能影响认知损伤 和神经变性。 App，A40和A42在病毒感染中也可能很重要，并且AD患者可能 对病毒感染的敏感性改变了。我们将APP NL-G-F小鼠与针对人类的APOE越过 替换（TR）小鼠，并将使用这些小鼠进行拟议的研究。海马显示神经病理学 在WNV患者和C57BL/6J野生型小鼠中感染WNV菌株的大脑中 与白介素34（IL-34）相关的学习障碍 - 依赖于突触前终端的吞噬 病毒感染期间和之后的海马中活化的小胶质细胞。我们将确定是否事先暴露 WNV恶化了Happ/A诱导的行为改变以及6-- 以及以ApoE同工型的方式进行的12个月大的HAPP KI小鼠，这些效果是否为 与增强的神经炎症和小胶质细胞激活有关。我们包括新颖的无线温度 传感器可以分析WNV暴露后的体温和昼夜节律的传感器 Happ/aApoe同工型和年龄。我们还将评估血浆和大脑中的细胞因子和趋化因子。 神经炎症，神经元丧失和APP和Aβ的上调并非特定于AD和/或WNV感染。 虽然WNV和神经退行性发病机理之间存在显着的重叠，但已被理解 重要的是要提高我们对相似​​性的理解，因为这将有助于识别 针对AD和其他神经退行性疾病的新型生物标志物和治疗策略。该提议是 根据PAR-22-094和NOT-AG-21-039提交。