Investigating the role of long-term latent herpes simplex virus infection on APOE4-associated Alzheimer's disease pathogenesis

研究长期潜伏的单纯疱疹病毒感染对 APOE4 相关阿尔茨海默病发病机制的作用

• 批准号: 10740641
• 负责人: Anna Ruth Cliffe
• 金额: $ 83.15万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740641
• 关键词: Address; Adult; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Antiviral Agents; Antiviral Therapy; Apolipoprotein E; Automobile Driving; Bioinformatics; Biology; Brain; Brain region; Cells; Cognitive; Cognitive deficits; Collaborations; DNA Primase; Data; Dementia; Development; Disease Progression; Disease susceptibility; Elderly; Exhibits; Future; Genes; Genotype; Gliosis; Goals; Health Care Costs; Herpes Simplex Infections; Herpesvirus 1; Hippocampus; Immunology; Impaired cognition; In Vitro; Individual; Infection; Inflammatory; Iron; Late Onset Alzheimer Disease; Literature; Long-Term Effects; Memory; Memory impairment; Modeling; Mus; Neurodegenerative Disorders; Neurons; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Permeability; Persons; Physiological; Population; Positioning Attribute; Primary Infection; Protein Isoforms; Protocols documentation; Research; Resolution; Risk; Risk Factors; Role; Series; Simplexvirus; Testing; Time; Treatment Protocols; Viral; acute infection; anti-viral efficacy; apolipoprotein E-4; brain cell; brain tissue; cell type; cognitive function; cognitive performance; efficacy evaluation; epidemiology study; experience; experimental study; follow-up; gene network; helicase; high risk; human old age (65+); in vitro Model; in vivo; inhibitor; interest; latent infection; neuroinflammation; novel; novel therapeutic intervention; prevent; spatial memory; synergism; tau Proteins; transcriptome sequencing; transcriptomics; translational study

Project Summary 47 million people worldwide are living with Alzheimer's disease (AD) or a related form of dementia. In the US alone, the annual health care costs for people with AD will exceed 1 trillion dollars by 2050. However, current treatments do not robustly prevent disease progression. The major risk factors for the late-onset form of AD are advanced age and possession of the ε4 allele of apolipoprotein E (APOE). Importantly, increasing data support the hypothesis that latent herpes simplex virus 1 (HSV-1) infection is also a risk factor, especially in combination with the APOE4 allele. This suggests that current antivirals may halt or delay neurodegenerative disease progression in APOE4 carriers who are infected with HSV-1. A major gap in the study of this association, however, is the absence of an HSV infection model reflecting the complexity of long-term latent infection, particularly in the context of APOE4 and AD. In our preliminary studies, we observed that HSV-1-infected APOE4 mice, compared to mock-infected APOE4 mice and HSV-1-infected WT mice, displayed robust spatial memory deficits, as well as oxidative stress, iron dysregulation, and gliosis in the CNS when assessed 15 months post infection (mpi), but not at 3 mpi. The objective of this proposal is to use this model, as well as complementary in vitro models, to fully elucidate the effects of long-term latent HSV-1 infection, in the context of differential APOE isoform expression, on brain function and AD pathogenesis. We will also assess whether treatment with a novel, brain-penetrant antiviral medication can block these effects. We anticipate that the full study proposed herein will uncover unique and important interactions between HSV-1 infection and APOE genotype in driving AD pathogenesis, potentially leading to safe and effective new therapeutic strategies for preventing or slowing AD in at-risk individuals.

项目概要 在美国，全世界有 4700 万人患有阿尔茨海默病 (AD) 或相关形式的痴呆症。 仅到 2050 年，每年用于 AD 患者的医疗费用就将超过 1 万亿美元。 治疗不能有力地阻止疾病进展。迟发性 AD 的主要危险因素是。 高龄和载脂蛋白 E (APOE) ε4 等位基因的拥有 重要的是，增加数据支持。 假设潜伏的单纯疱疹病毒 1 (HSV-1) 感染也是一个危险因素，尤其是合并感染时 这表明当前的抗病毒药物可能会阻止或延缓神经退行性疾病。 感染 HSV-1 的 APOE4 携带者的进展是这种关联研究中的一个主要空白， 然而，HSV感染模型的缺乏反映了长期潜伏感染的复杂性， 特别是在 APOE4 和 AD 的背景下，在我们的初步研究中，我们观察到 HSV-1 感染的 APOE4。 与模拟感染的 APOE4 小鼠和感染 HSV-1 的 WT 小鼠相比，小鼠表现出强大的空间记忆 15 个月后评估时，发现中枢神经系统的缺陷以及氧化应激、铁失调和神经胶质增生 感染（mpi），但不是 3 mpi 该提案的目标是使用该模型，以及补充。 体外模型，在差异 APOE 的背景下充分阐明长期潜伏 HSV-1 感染的影响 我们还将评估是否采用新的治疗方法。 我们预计本文提出的完整研究可以通过脑渗透性抗病毒药物来阻止这些影响。 将揭示 HSV-1 感染与 APOE 基因型之间在 AD 驱动过程中独特且重要的相互作用 发病机制，可能导致预防或减缓 AD 的安全有效的新治疗策略 在高危人群中。