R01AG073291

MECHANISM OF PATHOLOGIC TAU FIBRILS NEURON-TO-NEURON TRANSMISSION AND NEUROINFLAMMATION IN ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT:

NEUROFIBRILLARY TANGLES (NFTS) AS A HALLMARK PATHOLOGY OF ALZHEIMER'S DISEASE (AD) ARE WIDELY DISTRIBUTED IN THE AD BRAIN. THE MAJOR CONSTITUENT OF NFTS IS ABNORMAL TAU AGGREGATES FILLING THE INTRANEURONAL AND GLIAL CELL BODY.

EMERGING EVIDENCE INDICATED THAT PATHOLOGIC TAU FIBRILS ARE CAPABLE OF TRIGGERING A SELF-PROPAGATING PROCESS IN NEURONS AND OTHER BRAIN CELLS THAT LEADS TO NEURODEGENERATION AND NEUROINFLAMMATION.

EXPERIMENTAL DATA HAVE SHOWN THAT INTRACRANIAL INJECTION OF PATHOLOGIC TAU FIBRILS EXTRACTED FROM AD BRAINS RESULTS IN SUBSTANTIAL SPREADING OF TAU PATHOLOGY IN MOUSE BRAINS AND INDUCES BEHAVIORAL DEFICITS. HOWEVER, THERAPEUTIC TARGETS TO BLOCK THIS PATHOLOGIC TAU SPREADING HAVE NOT BEEN IDENTIFIED.

WE IDENTIFIED FOR THE FIRST TIME THAT LYMPHOCYTE-ACTIVATION GENE 3 (LAG3) IS AN ESSENTIAL RECEPTOR MEDIATING THE PATHOLOGIC A-SYNUCLEIN TRANSMISSION. OUR PRELIMINARY STUDIES FURTHER SUPPORT THAT LAG3, AS A CELL SURFACE RECEPTOR, MEDIATES THE TRANSMISSION OF TAU FIBRILS AND PATHOLOGIC TAU-INDUCED NEURONAL AND MICROGLIAL DEFICITS.

THESE RESULTS SUGGEST THAT LAG3 MAY SERVE AS A NOVEL TARGET FOR BLOCKING PATHOGENIC TAU SPREADING FOR THERAPEUTIC DEVELOPMENT. WE HAVE ESTABLISHED TWO MOUSE MODELS OF PATHOLOGIC TAU SPREADING WITH VALIDATED NEURONAL AND BEHAVIORAL DEFICITS AS WELL AS NEUROINFLAMMATORY RESPONSE.

OF NOTE, OUR PRELIMINARY DATA SUGGESTS THAT LAG3 PROTEIN IS EXPRESSED BOTH IN NEURONS AND MICROGLIA, AND DEPLETION OF LAG3 CAN INHIBIT TAU NEURONAL PROPAGATION AND MICROGLIAL ACTIVATION. ALL THESE RESULTS SUPPORT OUR CENTRAL HYPOTHESIS THAT LAG3 IS AN ESSENTIAL RECEPTOR OF PATHOLOGIC TAU IN NEURONS AND MICROGLIA THAT MEDIATES TAU INTERNALIZATION, TRANSMISSION AND TAUOPATHY.

NOW, IT IS FEASIBLE TO EXPLORE THE ROLE OF LAG3 IN FACILITATING TAU PATHOGENESIS AND THE THERAPEUTIC EFFICACY OF LAG3 TARGETING VIA GENETIC DELETION AND MONOCLONAL ANTIBODIES. OUR GOALS ARE (1) TO DEFINE THE ROLE OF LAG3 IN MEDIATING INTERNALIZATION OF PATHOLOGIC TAU AND THE CONSEQUENT NEURONAL AND MICROGLIAL RESPONSES INVOLVED IN THE PATHOGENESIS OF AD AND OTHER TAUOPATHIES, AND (2) TO DEVELOP A CLINICAL TRANSLATABLE STRATEGY TO INHIBIT LAG3-MEDIATED TAU PATHOGENESIS FOR THE TREATMENT OF TAUOPATHIES.

IF SUCCESSFUL, DISCOVERIES FROM THIS STUDY WILL IDENTIFY A CELL-SURFACE RECEPTOR THAT MEDIATES PATHOLOGIC TAU SPREADING AND SERVE AS A NOVEL THERAPEUTIC TARGET FOR THERAPEUTIC DEVELOPMENT. THIS PROJECT MAY ALSO PROVIDE NOVEL MOLECULAR INSIGHTS INTO KEY MEDIATORS OF PATHOLOGIC TAU SPREADING IN NEURONS AND OTHER BRAIN CELLS.

GIVEN THE ON-GOING CLINICAL TRIALS USING ANTI-LAG3 ANTIBODIES FOR CANCER IMMUNOTHERAPY, DISCOVERIES FROM THIS PROJECT WILL ALSO FACILITATE THE REPURPOSING OF THESE ANTI-LAG3 ANTIBODIES FOR TREATING AD AND OTHER TAUOPATHIES.

The Johns Hopkins University

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]

Baltimore, Maryland 212051832 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 397% from $634,859 to $3,154,208.