Understanding the functional impacts of Aβ variants in Alzheimer's disease with human brain organoids

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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.