Investigators
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 bringing together a new, multidisciplinary team of investigators, each providing distinct and complementary expertise. Dr. Martin Kampmann is an expert in the cell biology of Alzheimer’s disease and neurodegenerative diseases and has pioneered CRISPR screens in human neurons and other cell types relevant to brain disease. Dr. Daniel Southworth and Dr. Greg Merz are experts in the structural biology of protein aggregates and their interaction with cellular factors, and uses cutting-edge cryo-electron microscopy and tomography approaches to characterize aggregate structure in isolation and in the context of cells. Dr. William Seeley is a neurologist and neuroscientist who is an expert in the pathology of neurodegenerative diseases and the vulnerability of specific neurons in the human brain to protein aggregation and degeneration. He directs the UCSF Neurodegenerative Disease Brain Bank, provides a unique resource for characterizing tau aggregation in different diseases and validating findings from lab experiments in human brain tissues. Dr Sarah Kaufman is an expert in tau strains, and provided the first evidence that tau aggregates from different tauopathies act as prion-like strains.
The Hillblom Network for Tau Strain Mechanisms is 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 a unique platform developed by the investigators. Using CRISPR screens, cellular factors controlling the accumulation of specific tau strains are 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.