R01AG080667

Molecular and cellular underpinnings of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (Late-NC) - Project Summary/Abstract

Late-NC (limbic-predominant age-related transactive response DNA-binding protein of 43 kDa [TDP-43] encephalopathy neuropathological change), a recently recognized form of TDP-43 proteinopathy, is the third most impactful cause of dementia following Alzheimer's disease neuropathologic change (ADNC) and cerebrovascular disease, accounting for 15-20% of all dementia cases in older adults.

Genetic association studies by our group and others revealed unique, Late-NC-specific risk loci as well as those shared with other common dementia-causing proteinopathies. A transcriptomic study from our group implicated endo-lysosomal dysregulation as a crucial pathophysiologic process underlying Late-NC.

However, molecular and cellular underpinnings of Late-NC remain largely unknown: we do not even have the knowledge to develop in vitro/in vivo disease models or nominate target pathways, and as a result, we cannot diagnose, treat, or prevent Late-NC in living persons yet.

Defining molecular and cellular changes underlying Late-NC is a prerequisite to developing translational in vitro/in vivo disease models and identifying biomarker/therapeutic targets. This critical knowledge gap has been acknowledged by the NIH AD-Related Dementias (ADRD) Summit in 2022, which made a high-priority recommendation to investigate molecular changes associated with Late-NC.

Therefore, this proposal aims to define the transcriptomic, proteomic, and cellular underpinnings of Late-NC in the human amygdala, the brain region where Late-NC is thought to originate. Our central hypothesis is that, in the amygdala, endo-lysosomal dysregulation, altered RNA metabolism, glial dysfunction, and neuronal loss underlie Late-NC pathophysiology.

To test the central hypothesis, we propose to generate and analyze transcriptomic, proteomic, and single-nucleus multiome (transcriptome and chromatin accessibility) data from the post-mortem amygdala samples from the extensively characterized Religious Orders Study and Rush Memory and Aging Project participants (N=480).

We will pursue the following three specific aims: First, we will determine the transcriptomic underpinnings of Late-NC. Second, we will identify the proteomic signature of Late-NC. Third, we will define the single-cell landscape of Late-NC. We will use statistical modeling approaches to infer causal relationships. We will consider sex-specific effects and the confounding effect of comorbid ADNC pathology throughout the study.

The expected outcomes of this project will nominate protein biomarker targets and define plausible upstream and downstream events of Late-NC. These results will guide our future studies to develop in vitro and possibly in vivo Late-NC models and, eventually, targeted therapeutics.

The large-scale amygdala multi-omic data will be broadly shared with the scientific community to support numerous ADRD research projects, ensuring a significant lasting impact in neurodegeneration research far beyond this proposal.

Therefore, this project has the potential to fundamentally improve our ability to diagnose, treat, and ultimately prevent dementia, including Late.

Brigham & Womens Hospital

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 021156128 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)

Amendment Since initial award the total obligations have increased 199% from $1,296,013 to $3,870,802.