Investigating Mechanisms of Tau-Mediated Neurodegeneration in the Human Brain

We will apply single-cell technology to human brain samples with Alzheimer’s disease to investigate the contributions of distinct cell types to disease pathogenesis and identify the transcriptome changes associated with tau pathology. We will extend this work to other neurodegenerative tauopathies with the goals of uncovering the shared and distinct transcriptome alterations in tauopathies and define the molecular signatures of tau-mediated neurodegeneration. We will focus in preclinical and early-stage disease to identify the earliest, potentially upstream mechanisms; generate multi-omics data; and validate findings in brain tissue. Further comparisons between human samples and mouse models of disease will be pursued to identify evolutionary conserved mechanisms. Our overall goal is to provide improved frameworks for the study of neurodegenerative tauopathies by generating unbiased, comprehensive, and validated single-cell data from clinically relevant human tissue.