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

项目摘要 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。在美国 仅到2050年，阿尔茨海默病患者的年医疗费用就将超过1万亿美元。但是，当前 治疗并不能有力地阻止疾病的发展。晚发性AD的主要危险因素是 高龄和载脂蛋白E的ε4等位基因。重要的是，增加数据支持 假设潜伏的单纯疱疹病毒1型(HSV-1)感染也是一个危险因素，特别是在联合 携带APOE4等位基因。这表明目前的抗病毒药物可以阻止或延缓神经退行性疾病。 感染HSV-1的APOE4携带者的进展。这种联系研究中的一个重大空白， 然而，是否缺乏反映长期潜伏感染复杂性的HSV感染模型， 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APOE4的小鼠和感染HSV-1的WT小鼠相比，小鼠表现出强大的空间记忆 在15个月后评估中枢神经系统的缺陷以及氧化应激、铁失调和神经胶质细胞增多症 感染(MPI)，但不是在3MPI。这项提议的目标是使用这一模式，以及在 体外模型，在差异APOE的背景下，充分阐明长期潜伏的HSV-1感染的影响 异构体表达，对脑功能和AD发病机制的影响。我们还将评估一种新的、 脑穿透性抗病毒药物可以阻断这些作用。我们预计在此提出的完整研究 将揭示HSV-1感染和APOE基因在驱动AD中的独特和重要的相互作用 发病机制，可能导致安全有效的预防或减缓AD的新治疗策略 在高危人群中。

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.