Abstract Tauopathies consist of a group of diseases, including frontotemporal dementias and the most common form Alzheimer’s disease, and are characterized by the accumulation of intracellular neurofibrillary tangles (NFTs) composed of aggregates of hyperphosphorylated Tau protein and extensive neurodegeneration. Accumulating evidence has implicated impaired autophagy-lysosome pathway in neurodegenerative diseases including Alzheimer’s disease. The Transcription Factor EB (TFEB) was discovered as a master regulator of cellular clearance through coordinated expression of autophagy and lysosomal target genes. We have found that TFEB is highly efficacious in ameliorating Tau/NFT pathology and behavioral deficits in Tau transgenic mice while exhibiting no adverse effect on wild-type mice, supporting the premise that TFEB may serve as potential therapeutic target. The overarching goal of this project is to investigate a Tau-induced TFEB lysosome-to- nucleus signaling pathway regulating lysosomal homeostasis and cellular clearance in physiological and tauopathy conditions and to identify strategies to augment this pathway for enhanced cellular clearance. Specifically, through proteomics analysis of tauopathy mouse models, we will identify how Tau pathology induces unique TFEB post-translational modifications and nuclear signaling. By leveraging the powerful lysosomal purification and profiling system made available by the Program Project Grant investigators, we will test how Tau pathology alters the lysosomal proteome, metabolome, and pH, the latter is essential for lysosomal function and critically controlled by the vacuolar ATPase (V-ATPase). Accordingly, we will test the specific TFEB/V-ATPase signaling in Tau pathogenesis and downstream glia and immune response. This project is an integral component of the Program Project Grant aimed at understanding how lysosomal function is regulated through lysosome-to-nucleus signaling pathways, how these pathways are changed in aging and Alzheimer’s disease, and how to harness these regulatory pathways to promote brain health, combat age- associated functional decline, and delay neurodegenerative diseases. This project, together with the collaborative efforts of the Program Project Grant, will create a first-in-class Aging- and Tauopathy-associated Lysosomal atlas (ATLas) of the lysosomal proteome and metabolome for mouse cortex and hippocampus which will be made broadly available to the research community.