R01AG078929

Role of Transposon Dysregulation in Alzheimer and Aging Brains Revealed by Single-Cell Genomic and Transcriptomic Analysis - Project Summary

Aging in humans is associated with a host of brain diseases, including tumors, age-related neurodegeneration, and Alzheimer's disease (AD). In many tissues, the aging process leads to a derepression of transposable elements (TEs) that lead to inflammation and cell senescence.

Several recent studies have demonstrated that multiple subfamilies of TEs are expressed at higher levels in postmortem AD brain than healthy controls as a direct result of the accumulation of mis-folded tau proteins characteristic of AD pathology. Many of the hallmarks of AD, including neuroinflammation, heterochromatin remodeling, genomic instability, and the recently implicated T-cell infiltration, can be triggered by the activation of TEs.

However, because of the unique epigenomic landscape of different cell types in the brain combined with the dependence of TE mobilization on cell division and other factors, the dynamics and consequences of TE activation are likely cell-type-specific. This study aims to characterize the activation of TEs in the brain during aging and AD and identify the functional consequences of activated TEs at the level of individual cells across multiple cell types and to develop the novel computational tools necessary to answer these questions.

The first aim will establish the genomic and epigenomic changes related to TEs during normal aging. This analysis will help both to determine whether TEs are involved in the normal brain aging process and age-related neuronal decline, and to establish the healthy controls for comparison with AD.

The second aim will perform similar analysis, this time focusing on AD and including the separation of neurons with and without accumulation of pathogenic tau.

The final aim will measure the transcriptome at the single-cell level for all the samples profiled in the first two aims. This sequencing will allow both the measuring gene expression related to innate and adaptive immune responses and the identification of TE derived sequences capable of triggering those responses.

The experimental tools and sequencing technologies now exist to examine these questions, and this study is designed to determine how TE activation impacts normal brain aging and AD. Understanding the relationship between TEs, neuroinflammation, and AD pathology may open the door for new treatments and cures.

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

Elucidating the Roles of Transposable Elements in AD/ADRD and Aging (R01 Clinical Trial Not Allowed) (RFA-AG-22-021)

Amendment Since initial award the total obligations have increased 291% from $884,331 to $3,459,590.