Pathological deposition of abnormal aggregated tau protein in neurons is one of the diagnostic hallmarks of Alzheimer's disease (AD) and related dementia (ADRD). How pathological tau causes dysfunction and degeneration of neurons remains an enigma. However, neuronal dysfunction and neurodegeneration clearly cause dementia. To understand how abnormal tau contributes to neurodegeneration in AD and ADRD, we established a transgenic model in C. elegans for neurodegeneration driven by human tau aggregation. In our previous work, we identified XBP-1, the master transcriptional regulator of the unfolded protein response (UPR), as a critical regulator of pathological tau accumulation and toxicity. ER stress and activation of the UPR have clearly been implicated in human tauopathy disorders by other laboratories although the functional consequences of UPR activation on tau pathology remain unclear. We have leveraged our C. elegans model of tauopathy to dissect the functional role of the UPR in tau pathology. We have found that tau pathology can induce ER stress, and that UPR activation protects against tauopathy through XBP-1s. We hypothesize that XBP-1s target genes can modulate accumulation and clearance of pathological tau. To test this hypothesis, we upregulated the UPR in neurons in the absence of ER stress, using a constitutively active XBP-1s expressing transgene. Transcriptomic studies of this system have revealed key XBP-1s target genes that modulate tauopathy and cross talk with other regulatory branches of the UPR (ATF6 and PERK branches). Given the high level of conservation of the UPR system between mammals and C. elegans, we propose to utilize the existing model and transgenes to dissect the mechanism by which the UPR protects against tau neurotoxicity. The Specific Aims of this project are to: 1) Identify the molecular mechanisms of XBP1s mediated suppression of tauopathy; 2) Examine UPR branch crosstalk contributing to tau clearance and ER associated degradation, 3) Address the disease relevance of XBP-1s target genes to neurodegeneration in both human disease and mouse models of tauopathy. Completion of the project as proposed will inform the molecular mechanisms by which the UPR participates in tauopathy. We will also explore the neuroprotective translational potential of XBP-1s mediated tau clearance in the mammalian brain.