R01AG075955

Astrocyte and Neuron Brain-Region and Compartment-Specific Proteome Dynamics in Aging and Alzheimer's Disease

Alzheimer's Disease (AD) is a complex age-dependent disorder. It requires multiple approaches to comprehensively understand at a molecular level in order to develop novel diagnostics and disease-modifying treatments. Astrocytes and neurons coexist in the brain, and both major cell types are known to contribute to AD. The cellular phase of AD is proposed to comprise feedback and feedforward signaling between diverse brain cells as a link between the initial emergence of molecular pathology (abnormal tau and Aβ) and subsequent disease manifestations. Known glial cell proteins that contribute to this cellular phase are ApoE and TREM2, and are associated with a significantly increased risk of AD. Moreover, known astrocyte mechanisms include reactivity, which is a complex, non-binary phenomenon with sequelae that depend on context.

In the past, most disease-related studies have evaluated astrocytes or neurons using assessments of physiology, markers, or with gene expression evaluations. Astrocytes and neurons have not been studied in detail together or with cell-type specific proteomic methods, as proposed here and as requested by the FOA. As a result, despite advances, we have little precise information about the proteomes of astrocytes and neurons during aging in brain areas relevant to AD or in brain regions relevant to specific and defined abnormalities such as seizure activity in AD.

Our overarching hypothesis is that astrocytes and neurons display protein dynamics during normal aging and in mouse models of AD, and that these changes reflect signaling between these dominant brain cells during the cellular phase of AD pathogenesis and during aberrant seizure activity and its associated cognitive decline in AD.

Aim 1 will characterize cell, brain region, and compartment (plasma membrane versus cytosol) specific proteomic methods for astrocytes and neurons. Aim 2 will determine astrocyte and neuron proteomic dynamics during normal aging in mice. Aim 3 will determine astrocyte and neuron proteomic dynamics during aberrant network activity in AD model mice.

Understanding the identities and the extent of cell, brain region, and compartment-specific protein changes for the major brain cell types (astrocytes and neurons) using data-driven unbiased approaches could be foundational and catalytic with regards to new opportunities for translational and mechanistic work.

Los Angeles University Of California

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]

Los Angeles, California 900950001 United States

Single Zip Code

Regulation of Brain Regional and Cell Type Specific Proteome Dynamics in Aging and Alzheimer's Disease (R01 Clinical Trial Not Allowed) (RFA-AG-21-033)

Amendment Since initial award the total obligations have increased 409% from $1,031,564 to $5,247,255.