Age is the primary risk factor for numerous neurodegenerative diseases, with Alzheimer’s disease (AD) being the most prevalent. During aging there is a decline in protein quality control systems in general and the vacuolar dependent degradative pathways more specifically. Indeed, dysfunction of both autophagy and endolysosome systems occurs early in the pathogenesis of AD and impairment of these pathways likely contributes to the accumulation and mislocalization of tau, which plays an indispensable role in the pathogenesis of AD. Recent data provide compelling evidence that the stress responsive, multi-domain co- chaperone, Bcl-2-associated anthogene 3 (BAG3) plays a key role in maintaining proteostasis; decreased levels result in increased levels of phospho-tau and decreases in autophagosome-lysosome fusion. Further, our preliminary data indicate that BAG3 likely plays a key role in vacuolar dependent degradative processes beyond autophagy thus may be considered as a “master regulator” of neuronal proteostasis. The UNDERLYING PREMISE of this proposal is that in neurons BAG3 plays a critical role in mediating vacuolar dependent degradative pathways, and thus the turnover of tau. The importance of BAG3 in mediating neuronal proteostasis is illustrated by the fact that BAG3 not only plays a key role in protecting neurons from the accumulation of pathological tau species, but also facilitates the autophagic clearance of other disease relevant proteins such as α-synuclein. Nonetheless, our understanding of how BAG3 regulates autophagy and the endolysosome pathways is very limited. CRITICAL KNOWLEDGE GAPS include: understanding the specific impact of BAG3 on vacuolar-mediated proteostatic processes as a function of age, the role of BAG3 in mediating endocytosis, as well as how it regulates extracellular tau uptake and processing, and the role BAG3 in exosome formation and release, as well as the targeting of tau to this vesicular pool. Considering these critical knowledge gaps the OVERALL HYPOTHESIS of this proposal is that that BAG3 is a “proteostatic hub” that regulates vacuolar -based pathways to maintain a functional neuronal proteome. In the context of this overall hypothesis the specific aims of this proposal are: (1) To elucidate the role of BAG3 in mediating basal and stress-induced autophagy both in vitro and vivo, (2) To test the hypothesis that BAG3 regulates the endolysosome pathway and this impacts the processing of endogenous tau (including exosome formation and release, and targeting of tau to this pool) and (3) To test the hypothesis that BAG3 mediates endocytosis and thus uptake and trafficking of exogenous tau. These studies will be carried out using both primary neuron cultures and mouse models. All in vivo studies will be carried out in male and female mature, middle-aged and old mice to determine how age influences the effects of BAG3 on these vacuolar dependent degradative systems. The IMPACT of these studies will be to provide c...