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

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.