Explore roles of HSV-1 in Alzheimer's disease using mouse models

摘要 痴呆症是大脑记忆和认知的进行性丧失。阿尔茨海默病 (AD)是导致65岁以上老年痴呆症的主要原因。目前，约有5.6 65岁及以上的美国人有100万人患有AD，预计到2050年AD患者将增加一倍。 神经退行性疾病的社会和经济负担是巨大的，并且没有治愈或预防方法。 到目前为止，预防是可行的。迟发性AD占所有AD病例的98%以上，是一种 多因素疾病，年龄是最突出的风险因素。除了基因 在患者的组成中，环境因素，如微生物感染， AD的发展和结果。 疱疹病毒在人类中普遍存在，并且它们的感染在免疫系统中通常是无症状的。 有能力的人。最近的研究表明几种疱疹病毒的因果作用， 特别是单纯疱疹病毒1（HSV-1）在AD和其它相关痴呆中的作用。如何HSV-1 对AD发病机制的影响尚不清楚。在研究宿主的先天免疫， 在疱疹病毒中，我们发现了NAMPT，挽救NAD合成的限速酶 途径，有效地限制HSV-1裂解复制。NAMPT的缺失大大增加了HSV-1 在小鼠中复制。为了抵消NAMPT介导的限制，HSV-1进行脱酰胺化 抑制NAMPT并促进病毒复制。HSV-1诱导的免疫系统 逃避，脱酰胺NAMPT在合成NAD+中严重受损。因此，HSV-1诱导的 NAMPT脱酰胺和随后的NAD+补救合成受损可能有助于 HSV-1诱导的神经变性。有趣的是，老化也诱导NAMPT脱酰胺， 大脑在本研究中，我们将描述脱酰胺在宿主防御和挽救中的作用 神经元和小鼠中的NAD+合成。我们还将确定衰老和HSV-1感染 协同促进NAMPT脱酰胺和NAD+消耗，从而加速神经变性 在正常的小鼠品系中。最后，我们将开发一种抗NAMPT脱酰胺的方法， 阻止或逆转神经变性和AD的发展。这项研究将阐明一个 病毒免疫逃避和衰老附带损害的创新机制 合作诱导神经退行性变，提供新的见解，可能的途径，以阻挠 AD和其他与衰老和微生物感染相关的神经退行性疾病。

Abstract Dementia is the progressive loss in memory and cognition of the brain. Alzheimer’s disease (AD) is the leading cause of dementia in those over the age of 65. Currently, there are ~5.6 million Americans age 65 and older have AD, and the projected AD patients will double by 2050. The social and economic burden of neurodegenerative diseases is enormous and no cure or prevention is available to date. Late onset AD accounts more than 98% of all AD cases and is a multifactorial disease, with aging being the most prominent risk factor. In addition to the genetic makeup of a patient, environmental factors, such as microbial infection, contribute significantly to the development and outcome of AD. Herpesviruses are ubiquitous in human and their infection is often asymptomatic in immune- competent individuals. Recent studies suggest a causal role of several herpesviruses, particularly herpes simplex virus 1 (HSV-1), in AD and other related dementia. How HSV-1 contributes to AD pathogenesis is not well understood. In studying host innate immunity against herpesvirus, we discovered that NAMPT, the rate-limiting enzyme of the salvage NAD synthesis pathway, potently restricts HSV-1 lytic replication. Loss of NAMPT greatly increases HSV-1 replication in mice. To counteract the NAMPT-mediated restriction, HSV-1 deploys deamidation to inactivate NAMPT and promote viral replication. Collateral to the HSV-1-induced immune evasion, deamidated NAMPT is severely impaired in synthesizing NAD+. Thus, HSV-1-induced NAMPT deamidation and subsequent impaired salvage synthesis of NAD+ likely contribute to the HSV-1-induced neurodegeneration. Interestingly, aging also induces NAMPT deamidation in the brain. In this study, we will delineate the role of deamidation in host defense and salvage NAD+ synthesis in neurons and in mice. We will also determine how aging and HSV-1 infection synergize to promote NAMPT deamidation and NAD+ depletion, thus fueling neurodegeneration in normal mouse strains. Finally, we will develop a modality to resist NAMPT deamidation that impedes or reverts neurodegeneration and AD development. This study will elucidate an innovative mechanism by which collateral damage of viral immune evasion and aging collaborate to induce neurodegeneration, offering new insight into possible avenues to thwart AD and other neurodegenerative diseases associated with aging and microbial infection.