Wednesday, April 24, 2024
4/24/2024
While the AD etiology remains largely unknown, with no effective strategy to arrest the relentless progression of the disease, current evidence connects amyloid-ß (Aß), 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 Aß 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 Aß 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 Aß propagons. In the current application, we will combine our complementary areas of expertise to analyze the assembly and propagation of Aß 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 Aß assemblies define dynamic kinetic stability underlying the pathobiology of the self-perpetuating amyloid strains of AD. First, we will identify strain-specific patterns of Aß intracellular formation and propagation to correlate the molecular foundations of structural differences among Aß strains (Aim 1). Second, we will determine the biochemical manifestation of Aß 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 Aß 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
