Abstract

A hallmark of Alzheimer’s disease and several other age-associated neurodegenerative diseases is the misfolding and aggregation of the protein tau. Tau aggregation is closely associated with the degeneration of neurons, and genetic mutations in tau can cause inherited neurodegenerative disease. Therefore, tau is considered a key molecular driver of these diseases. Recently, advances in electron microscopy have highlighted distinct tau aggregate structures (or tau “strains”) in pathologically distinct tauopathies. It remains unknown, however, how these distinct tau strains form in the aging brain or how they contribute to cell- and region-specific degeneration. Understanding these mechanisms would deepen our understanding of Alzheimer’s disease and other age-associated neurodegenerative diseases and inform the development of new therapies. The Hillblom Network for Tau Strain Mechanisms is addressing this urgent need by characterizing different tau strains and their interaction with human neurons in post-mortem patient brain tissues and in human neurons in a culture dish. Using CRISPR screens, cellular factors controlling the accumulation of specific tau strains will be identified and characterized. We will test the therapeutic potential of these factors by targeting them pharmacologically. We will then determine whether these factors may be drivers of selective vulnerability in humans, based on experimental neuropathology approaches. The insights from this research will pave the way for novel therapeutic approaches enhancing the clearance of specific disease-relevant tau strains.