Project Summary Alzheimer's disease is a terminal neurodegenerative disease that is characterized by multiple neuropathological hallmarks and the diagnostic accumulation of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plagues. NFTs arise form the aggregation of phosphorylated Tau and have been observed in familial mutants thereof. Other forms of neurodegeneration associated with tauopathy include frontotemporal dementia and chronic traumatic encephalopathy. The main line of defense against protein aggregation in the cell is the chaperone function of a group of heat shock proteins. The ATP-independent small heat shock proteins (sHSPs) are tasked by the rapid and efficient buffering of aggregation-prone protein. Despite evidence of involvement of sHSPs in many neurogenerative diseases including AD, a mechanistic understanding of the interaction between sHSP and aggregation-prone Tau is lacking. This supplement request will expand our efforts on the parent grant, EY12018, which is focused on deciphering the physiological roles of HspB1, HspB4 and HspB5, to include the interactions of these sHSPs with aggregation-prone Tau. The research plan will bring to bear an integrated perspective emphasizing zebrafish genetics, fluorescence imaging and biochemical analysis of binding by sHSPs which has proven successful in elucidating molecular events associated with another aging-related protein aggregation disease, lens cataracts. It will take advantage of the simplicity of terminally differentiated lens fiber cells to characterize the interaction of tau with sHSPs in a living animal. The research plan will investigate the effects of changes in chaperone capacity of sHSPs as well as oxidative stress on the aggregation of tau. Together, the data will address an unexplored aspect of neurodegeneration in the unique model of the zebrafish lens. The results will provide potential therapeutic strategies to interfere with tauopathies.