R24AG073205

Genetic Models of Sporadic Alzheimer's Disease in the Marmoset - Abstract

The long-term goal of this project is to develop, characterize, and validate genetically modified marmoset models of sporadic Alzheimer's disease (AD) that will serve as tools for investigating molecular and cellular disease mechanisms, and for identifying therapeutic targets.

AD is the most common cause of dementia, with the majority of cases (~95%) appearing to be sporadic, which is caused by complex interactions between multiple gene variants and environmental factors. Numerous models of AD have been developed (e.g., mice); these models are primarily focused on familial forms of AD and have enabled significant progress toward understanding AD, but they fail to recapitulate the full spectrum of molecular, cellular, behavioral, and cognitive pathologies observed in AD and provide poor predictive value when trying to translate findings to human clinical trials.

Several lines of evidence suggest that marmosets may effectively bridge the gap between mice and humans for both basic and translational neuroscience research. First, marmosets and humans have very similar brain structures, cognitive/social behavioral repertoires, metabolism, and immune functions. Second, compared to other primates, marmosets have a short lifespan, small body size, and high reproductive power. Finally, gene editing tools are now available to generate various types of genetically modified marmosets.

Apolipoprotein E (APOE) is the strongest risk factor for late-onset, sporadic AD and also increases the age-dependent risk of monogenic familial AD and incidence of AD in women. There are three APOE alleles in humans with the APOE*E4 allele conferring increased risk and the APOE*E2 allele conferring decreased risk relative to the common APOE*E3 allele. APOE isoforms differentially modulate both amyloid-β (Aβ)-dependent and Aβ-independent pathways to affect brain homeostasis, including tau-mediated neurodegeneration, microglial inflammation, lipid transport, synaptic integrity, glucose metabolism, and cerebrovascular function. These three APOE alleles differ with regard to cysteine (C) and arginine (R) amino acids at positions 112 and 158 (C112/C158 in APOE2; C112/R158 in APOE3; and R112/R158 in APOE4). Several lines of evidence demonstrate that R61 is critical for APOE4-mediated AD risk.

Marmoset APOE (MAPOE) is encoded by a single allele and contains the equivalent of R112 and R158 but lacks the critical R61 equivalent (it contains T instead), suggesting that it behaves like human APOE3. To test this hypothesis, MAPOE T61R mutant protein was generated to test the effect on inflammatory responses induced by lipopolysaccharides in microglial cells. The MAPOE T61R variant resulted in a more robust response compared to wild-type MAPOE. Similar results were found when human APOE4 was used (APOE4>APOE3). Taken together, these preliminary results indicate that MAPOE T61R is functionally equivalent to human APOE4.

Furthermore, several pairs of CRISPR gRNAs for generating an APOE null mutation have been identified. To investigate the role of APOE in sporadic AD in the marmoset, APOE null and T61R mutant marmosets will be generated and characterized.

San Diego, California Salk Institute For Biological Studies

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]

La Jolla, California 92037 United States

Single Zip Code

New/Unconventional Animal Models of Alzheimers Disease (R24 Clinical Trial Not Allowed) (RFA-AG-21-003)

Amendment Since initial award the End Date has been extended from 06/30/25 to 06/30/26 and the total obligations have increased 308% from $1,410,426 to $5,749,378.