Structural determinants of amyloid strain heterogeneity in distinct phenotypes of Alzheimer's disease

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The deposition of aggregated hyperphosphorylated tau protein in brain is directly associated with cell death and propagation of brain pathology in Alzheimer's disease and several other neurodegenerative diseases, including frontotemporal dementia. The major goal of the parent award RF1 AG 061797 is to elucidate the relationship between structural properties of tau and Aβ aggregates and phenotypic variability of Alzheimer's disease and related disorders. An important recent development is the finding that, akin to some other proteins involved in neurodegenerative diseases, tau can undergo liquid-liquid phase separation, forming condensates in which protein concentration is extremely high. The environment of these condensates may have a major impact on the aggregation properies of tau, contributing to the pathogenic process. The purpose of this Administrative Supplement is to expand the scope of studies in the parent award into this rapidly emerging area of research, with the main specific objective to elucidate the mechanisms of tau liquid-liquid phase separation and the role of different types of interactions in this process. The insights gained in this research should provide a necessary foundation for future studies aimed at understanding the intricate role of liquid-liquid phase separation in pathological aggregation of tau in Alzheimer's disease and related disorders.