RF1AG037491

UNDERSTANDING THE ROLE OF TDP-43 IN ALZHEIMER’S DISEASE, FTLD AND RELATED DISORDERS - PROJECT SUMMARY THE FIRST THREE CYCLES OF THE R01 FOCUSED ON ASSESSING THE INFLUENCE OF TDP-43 IN ALZHEIMER’S DISEASE (AD) AND FRONTOTEMPORAL LOBAR DEGENERATION. WE HAVE BEEN VERY SUCCESSFUL WITH OVER 138 PEER-REVIEWED PUBLICATIONS AND MANY NOVEL DISCOVERIES. WE DEMONSTRATED, FOR EXAMPLE, THAT TDP-43 IN ALZHEIMER’S DISEASE IS ASSOCIATED WITH FASTER RATES OF BRAIN ATROPHY 15 YEARS BEFORE DEATH, AND HYPOMETABOLISM ON [18F] FDG PET IN MEDIAL TEMPORAL AND FRONTAL REGIONS. WE ALSO IDENTIFIED ATYPICAL TDP-43 INCLUSIONS CHARACTERIZED BY FULL- LENGTH TDP-43. WHETHER SUCH INCLUSIONS ARE PATHOLOGIC OR PLAY ANY ROLE IN NEURODEGENERATION IS UNKNOWN. FURTHERMORE, LITTLE IS KNOWN ABOUT TDP-43 IN OTHER NEURODEGENERATIVE DISEASES SUCH AS LEWY BODY DISEASE AND 4-REPEAT TAUOPATHIES, INCLUDING PROGRESSIVE SUPRANUCLEAR PALSY AND CORTICOBASAL DEGENERATION. RECENTLY, THERE HAS BEEN A MAJOR DISCOVERY THAT LINKED TDP-43 TO NON-CONSERVED INTRONIC SEQUENCES KNOWN AS CRYPTIC EXONS. NORMAL TDP-43 INHIBITS THE SPLICING OF CRYPTIC EXONS INTO THE TRANSCRIPT WHILE PATHOLOGIC TDP-43 LEADS TO A TRANSCRIPT WITH INSERTED CRYPTIC EXONS. THIS RESULTS IN FORMATION OF NON-FUNCTIONAL PEPTIDES OR DESTRUCTION OF PEPTIDES BY NONSENSE MEDIATED DECAY. CRYPTIC EXONS HAVE BEEN IDENTIFIED IN ALS, FRONTOTEMPORAL LOBAR DEGENERATION AND ALZHEIMER’S DISEASE. IN THE 4TH CYCLE OF THE R01, THE MAIN GOAL IS TO UNDERSTAND RELATIONSHIPS BETWEEN TDP-43 AND CRYPTIC EXONS AND HOW THEY INFLUENCE NEURODEGENERATIVE DISEASE. IN AIM 1, WE WILL INVESTIGATE WHETHER CRYPTIC EXONS ARE RELATED TO TDP-43 IN LEWY BODY DISEASE AND 4-REPEAT TAUOPATHIES AND DETERMINE WHETHER CRYPTIC EXONS ARE ASSOCIATED WITH ATYPICAL INCLUSIONS. IN AIM 2, WE WILL FURTHER OUR STUDIES ON TDP-43 ASSOCIATED BRAIN CHANGES BY INVESTIGATING WHETHER TDP-43 IMPACTS NETWORK CONNECTIVITY WITHIN THE BRAIN. WE WILL UTILIZE DIFFUSION TRACTOGRAPHY AND NEURITE ORIENTATION DISPERSION AND DENSITY IMAGING (NODDI) TO ASSESS MICROSTRUCTURAL ABNORMALITIES IN WHITE MATTER TRACTS, AND RESTING STATE FMRI TO ASSESS FUNCTIONAL CONNECTIVITY WITHIN NETWORKS AND BETWEEN BRAIN REGIONS. UNDERSTANDING RELATIONSHIPS BETWEEN TDP-43 AND DISRUPTED CONNECTIVITY WOULD HELP US TO UNDERSTAND SPREADING MECHANISMS AND HOW BREAKDOWN OF BRAIN NETWORKS IN NEURODEGENERATIVE DISEASES ARE RELATED TO TDP-43. WE WILL ALSO INVESTIGATE WHETHER ASSOCIATIONS BETWEEN TDP-43 AND CLINICO-IMAGING FEATURES SUCH AS MEMORY LOSS AND HIPPOCAMPAL ATROPHY ARE MEDIATED BY CRYPTIC EXONS. LASTLY, AS WE MOVE TOWARDS THERAPEUTIC TARGETS FOR PROTEIN DEPOSITION IN NEURODEGENERATIVE DISEASES, IT IS IMPORTANT TO HAVE BIOMARKERS FOR TDP-43. CURRENTLY, NO SUCH BIOMARKER EXISTS WHICH IS A MAJOR LIMITATION FOR TDP-43 RELATED CLINICAL TRIALS. IN AIM 3, WE WILL COMBINE GENETIC INFORMATION ON THE TRANSMEMBRANE PROTEIN 106B AND APOLIPOPROTEIN GENOTYPE WITH CRYPTIC EXONS TO DETERMINE WHETHER SUCH A BIOMARKER WOULD ACCURATELY PREDICT TDP-43, BETTER THAN MRI AND [18F] FLUORODEOXYGLUCOSE PET. ACHIEVING THESE AIMS WOULD UNCOVER MECHANISTIC EFFECTS OF TDP-43 IN NEURODEGENERATIVE DISEASE, HAVE A SIGNIFICANT IMPACT ON DEVELOPMENT OF TDP-43 TARGETED TREATMENT, AND ON THE EXECUTION OF CLINICAL TRIALS TARGETING TDP-43.

Mayo Clinic

<P>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.</P>

93.866 - Aging Research

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

Rochester, Minnesota 559050001 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-25-332)