RF1AG090712

ROLE OF THE RETROSPLENIAL CORTEX IN THE PROGRESSION OF AD PATHOGENESIS IN MOUSE AND HUMAN - PROJECT SUMMARY WHILE RECENT IMMUNOTHERAPIES FOR ALZHEIMER’S DISEASE (AD) HAVE SHOWN PROMISE, THEY COME WITH SIGNIFICANT SIDE EFFECTS AND MAY NOT WORK EQUALLY WELL FOR PATIENTS AT DIFFERENT STAGES OF AD. THIS NECESSITATES A CONTINUED FOCUS ON THE DEVELOPMENT OF AD THERAPEUTICS, ESPECIALLY ON IDENTIFYING THE EARLIEST DRIVERS OF AD. FIRST, IT IS CRITICAL THAT WE KNOW WHERE IN THE BRAIN TO FIND THE EARLIEST EVENTS THAT CONTRIBUTE TO AD PATHOGENESIS. EVIDENCE FROM HUMAN LITERATURE INDICATES THAT THE DEFAULT MODE NETWORK, IN PARTICULAR THE RETROSPLENIAL CORTEX/POSTERIOR CINGULATE GYRUS (RSC/PCC)/PRECUNEUS REGIONS, SHOWS EARLY AMYLOID DEPOSITION WITH CONCOMITANT ELEVATIONS IN METABOLISM, THOUGH THE FUNCTIONAL IMPLICATIONS OF THIS OBSERVATION ARE UNKNOWN. ANECDOTAL EVIDENCE ALSO SUGGESTS THAT SPATIAL NAVIGATION MAY BE AMONGST THE EARLIEST IMPAIRMENTS OBSERVED IN PRECLINICAL AD, WHICH IS CONSISTENT WITH DYSFUNCTION OF RSC. THESE FINDINGS ALL POINT TO A POTENTIALLY IMPORTANT ROLE OF THE RSC IN AD PATHOGENESIS, YET WHAT IS OCCURRING IN THE RSC, WHEN IT OCCURS, AND HOW IT MAY CONTRIBUTE TO AD-RELATED DISEASE HAS NOT BEEN EXPLORED. IN THIS PROPOSAL, WE WILL DEFINE HOW NEURONAL HYPEREXCITABILITY IN THE RSC CONTRIBUTES TO THE DEVELOPMENT OF AD- RELATED BEHAVIORAL DEFICITS IN MICE, AND THE MOLECULAR MECHANISMS THAT UNDERLIE THIS EFFECT. OUR PILOT DATA PROVIDE STRONG SUPPORT FOR A CAUSATIVE ROLE OF HYPEREXCITABILITY IN RSC LAYER 5 CELLS IN THE DISEASE-ASSOCIATED LOSS OF MEMORY IN MICE, AS SILENCING RSC LAYER 5 CELLS PREVENTED THE AGE-ASSOCIATED LOSS OF MEMORY RECALL IN AD MODEL MICE. IN THIS APPLICATION, WE WILL FIRST DEFINE THE EFFECT OF INHIBITION OF RSC LAYER 5 CELLS ON HIPPOCAMPUS-ASSOCIATED SPATIAL MEMORY AND SPATIAL NAVIGATION TASKS, AND TEST WHEN HYPEREXCITABILITY EMERGES IN THESE CELLS IN AIM 1. THIS WILL BE DONE IN 3 DIFFERENT MOUSE MODELS, INCLUDING AMYLOID AND TAU MODELS. IN AIM 2 WE WILL EXPLORE THE TRANSCRIPTIONAL CHANGES THAT OCCUR IN THE RSC DURING DISEASE PROGRESSION IN THREE DIFFERENT MOUSE AD MODELS. IN AIM 3, WE WILL ASSESS THE TRANSCRIPTIONAL CHANGES THAT OCCUR IN THE HUMAN RSC USING HUMAN POSTMORTEM SAMPLES FROM CONTROL, MILD COGNITIVE IMPAIRMENT, AND AD PATIENTS. WE WILL FOCUS ON IDENTIFICATION OF CONSERVED GENE EXPRESSION MODULES THAT CHANGE DURING THE DEVELOPMENT OF AD IN THE MOUSE AND HUMAN BRAIN, VALIDATING OUR RESULTS USING SPATIAL TRANSCRIPTOMICS AND IMMUNOHISTOCHEMICAL VALIDATION. THIS STUDY WILL PROVIDE SUPPORT FOR A CRITICAL ROLE THAT RSC HYPEREXCITABILITY PLAYS IN AD PROGRESSION, AND A MECHANISTIC FRAMEWORK FOR HOW CHANGES IN INTRINSIC EXCITABILITY AND SYNAPTIC FUNCTION CONTRIBUTE TO THE DEVELOPMENT OF AD.

Irvine University Of 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]

Irvine, California 92697 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)