R01AG072599

Selective interactome vulnerability across the Alzheimer's disease spectrum - Abstract

Mechanisms underlying selective vulnerability from cells to networks across the Alzheimer's disease (AD) spectrum remain unknown, limiting our understanding of disease and hampering development of effective therapies.

We propose to identify protein-protein interaction (PPI) network dysfunctions in brain cells and regions as a gateway to selective vulnerability mechanisms in AD. To gain systems level insights, we propose to leverage our discoveries in stress biology linking interactome network perturbations to the formation of long-lived oligomeric scaffolds termed epichaperomes, and to employ a novel 'omics platform called epichaperomics that provides direct information on PPI network changes.

Preliminary studies indicate epichaperomes change how thousands of proteins interact and negatively impact PPI networks important for neuronal function, including synaptic plasticity, cell-to-cell communication, protein translation, cell cycle re-entry, axon guidance, metabolic processes, and inflammation, leading to cell and connectome-wide dysfunction and cognitive decline.

Parallel studies in transgenic mice and iPSC-derived neurons demonstrate epichaperome formation is a key event that negatively impacts cellular function, from early prodromal disease stages and throughout disease progression. Preliminary results in transgenic mice and postmortem AD brains suggest epichaperome formation occurs principally within vulnerable brain cells and regions.

Accordingly, we hypothesize epichaperome formation, and in turn, epichaperome-mediated PPI network imbalances, over decades, not only results in defects within intrinsic neuronal proteins and protein pathways but also intercellularly, where it disrupts intrinsic network connectivity of cells and of brain circuits. We posit vulnerable neurons and brain regions have a higher propensity to accumulate epichaperomes and epichaperome-mediated dysfunctions.

In accordance with NOT-AG-21-040, we propose to uncover mechanisms of PPI dysfunctions within individual brain cells and regions as a portal into selective vulnerability in AD, which remains unknown and a key missing piece. We aim to i) investigate mechanisms that enable (i.e., epichaperomes, Aim 1) and ii) those that execute (i.e., impacted proteins and protein pathways, Aim 2) context-specific dysfunctions in PPI networks. As a key element in linking stressors to phenotype, we aim to uncover cell- and region-specific vulnerabilities within PPI networks induced by individual stressors (Aim 3).

Results provide first-of-a-kind insights into the spatio-temporal formation and distribution of epichaperomes across the AD spectrum and their relationship to clinical, pathologic, and genetic vulnerabilities. Outcomes are critical proteome-wide insights into interactome vulnerabilities, both on the nature and trajectory within vulnerable brain cells and brain regions.

Raw datasets and data analytics will be deposited directly into free access sites for mining and hypothesis testing by members of the scientific community. In addition to defining technically challenging mechanistic insights into selective AD vulnerabilities, innovation includes diagnostics and therapeutics, as epichaperome-mediated dysfunctions are both imageable and targetable.

Sloan-Kettering Institute For Cancer Research

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]

New York, New York 100656007 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 182% from $1,165,481 to $3,289,457.