R01AG070904

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 approximately 5.6 million Americans aged 65 and older who have AD, and it is projected that the number of AD patients will double by 2050. The social and economic burden of neurodegenerative diseases is enormous, and to date, there is no cure or prevention available.

Late-onset AD accounts for 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 humans, 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 dementias. However, 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 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.

University Of Southern California

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Los Angeles, California 900890058 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 394% from $798,664 to $3,945,285.