Aggregation of microtubule-associated protein tau is a hallmark of age-dependent neurodegeneration in Alzheimer’s disease and other tauopathies. While tau mutations are strongly associated with some tauopathies (e.g. frontotemporal dementia), the vast majority of cases with tauopathic neurodegeneration do not result from tau mutations: for example, no tau mutation is known to cause Alzheimer’s disease. Thus, there is a critical need to understand why wild type tau fails to retain its native conformation, and forms pathogenic oligomers and aggregates. Our objective here is to delineate the molecular mechanism of tau proteostasis, and how this mechanism modifies tau aggregation and neurodegeneration. Based upon our preliminary data in combination with published studies, our central hypothesis is that tau aggregation and neurodegeneration are reduced by three proteostatic mechanisms: via structural stabilization by the CSPα/Hsc70 “foladase” complex, via turnover by the CHIP/Hsc70 “degradase” complex, and/or via disaggregation by the Hsp110/Hsc70 complex. At the completion of our studies, we expect to have (i) determined in molecular detail, how CSPα stabilizes tau and affects tau aggregation, (ii) included this novel activity in the overall context of tau proteostasis: which of CSPα, CHIP and/or Hsp110 is most effective at reducing tau aggregates while maintaining native tau, and (iii) determined in vivo how these proteostatic mechanisms protect against tau-driven neurodegeneration.