RF1AG079256

Understanding the Functional Impacts of Aβ Variants in Alzheimer's Disease with Human Brain Organoids

While the AD etiology remains largely unknown, with no effective strategy to arrest the relentless progression of the disease, current evidence connects amyloid-β (Aβ), a 40/42 amino acid peptide, to early disease progression. How folding of this peptide might create the heterogeneous assemblies (strains) that propagate as a prion-like infection throughout the brain remains a central question.

Accordingly, we propose to connect the mechanisms of diversification and propagation of proteopathic Aβ strains to their biochemical manifestation to connect the structural foundation of strain patterns with disease etiology in human brain organoids. Because strains influence the pathogenic properties of disease etiology and because aggregated Aβ proteins may also govern therapeutic approaches to the diseases (such as immunotherapy), it is essential to structurally and functionally characterize what we now understand to be the dynamic nature of proteopathic Aβ propagons.

In the current application, we will combine our complementary areas of expertise to analyze the assembly and propagation of Aβ strains with their impact in human brain organoids (Z. Wen), spectroscopic analyses of the dynamic assembly network members (D. Lynn), and with high- and low-resolution cryo-EM reconstructions (B. Liang) to define critical disease propagons.

Our overarching hypothesis is that the multidimensional dynamics of Aβ assemblies define dynamic kinetic stability underlying the pathobiology of the self-perpetuating amyloid strains of AD.

First, we will identify strain-specific patterns of Aβ intracellular formation and propagation to correlate the molecular foundations of structural differences among Aβ strains (Aim 1).

Second, we will determine the biochemical manifestation of Aβ strains and elucidate the underlying mechanisms by which aberrant strains function in the human cortical organoid model (Aim 2).

Lastly, we will delineate the molecular signatures associated with Aβ strains in human cortical organoids (Aim 3).

By combining the advanced human induced pluripotent stem cell technology with comprehensive structural and functional analyses, our investigation will reveal key structural features underlying the propagation of misfolded protein aggregates in Alzheimer's disease, allowing us ultimately to identify early neurodegenerative AD etiology targets for therapeutic intervention.

Emory University

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]

Atlanta, Georgia 303221047 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 End Date has been extended from 07/31/25 to 07/31/27 and the total obligations have increased 77% from $2,333,853 to $4,119,330.