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

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $798,803

## Abstract

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.

## Key facts

- **NIH application ID:** 10492490
- **Project number:** 5R01AG070904-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Pinghui Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $798,803
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492490

## Citation

> US National Institutes of Health, RePORTER application 10492490, Explore roles of HSV-1 in Alzheimer's disease using mouse models (5R01AG070904-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10492490. Licensed CC0.

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