R01AG071858

Integrated Platform to Study Neurodegeneration in Alzheimer's Disease - Project Summary/Abstract

In Alzheimer's Disease (AD), the accumulation of intracellular posttranslationally modified tau aggregates is a hallmark of AD pathology and a strong correlate of cognitive impairment. While the posttranslational modifications (PTMs) on tau in pathological aggregates have been studied for decades, our new quantitative and qualitative mass spectrometry approaches have discovered approximately 100 PTMs in the angular gyrus from 98 human Alzheimer's disease patients in these aggregates, specifically in Braak stages V/VI, compared to age-matched control subjects without pathological changes in the frontal lobe.

In this proposal, we aim to develop a large-scale proteomics platform to map the temporal occurrence of PTMs as the disease progresses. We will examine a valuable new set of cases, selected to encompass all Braak stages from 0 to VI. All cases in this new cohort will have detailed pre-mortem clinical data, which will allow us to detect and assess correlations between clinical and pathophysiological findings and any tau PTM identified in this study.

For this analysis, we will study three brain regions (entorhinal/amygdala, and temporal and visual cortex) in 20 Braak 0 subjects, 40 early stage Braak I/II subjects, 40 mid-stage Braak III/IV subjects, and 40 end-stage Braak V/VI subjects. We will also map the global proteomes of the brain specimens from this well-characterized patient cohort to identify the enzymes associated with these Braak stage-dependent PTMs. The findings of the tau characterization and mapping of the proteomes will be validated using widely accepted tau sensor assays used to study tau aggregation in AD.

In summary, this tau PTM-specific dataset, the deep proteome maps, and the subsequent validation experiments in seeding assays will be used to test our overarching hypothesis: understanding how the progressive accumulation of tau PTMs results in the toxicity and seeding competence of tau, and mapping the disease progression dependence of these PTMs and the enzymes responsible for them will allow us to develop interventional strategies at earlier and prodromal stages of the disease.

Children's Hospital Corporation

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]

Boston, Massachusetts 021155724 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 398% from $778,347 to $3,876,168.