U.S. Veterans are at increased risk for developing Alzheimer's disease (AD) pathologies and symptoms compared to the civilian population (1). The microtubule associated protein tau is a major contributor to the neuronal loss that occurs in the AD brain. As our recent publication shows, we have discovered a new mechanism that may be involved in tau-mediated neurotoxicity in AD: activation of the unfolded protein response (UPR)(2). We also found that PERK and some other components of the UPR are activated in transgenic tau mice. The UPR is also activated in the human AD brain, consistent with previous findings (3-6), confirming that tau accumulation without over-expression is sufficient to activate the UPR. One reason we have discovered for why this occurs is that soluble tau intermediates can inhibit endoplasmic reticulum (ER) associated degradation (ERAD) through aberrant interaction with the VCP/Hrd1 complex, which is necessary for normal ERAD. This faulty interaction causes ubiquitinated and misfolded ER proteins to accumulate, triggering the UPR, which in turn we speculate contributes to the neuronal death observed in tauopathies. Since the neuronal death in the AD brain far exceeds the burden of tau pathology (7), it suggests that soluble tau must trigger noxious events in the brain independent of detectable tangle pathology, such as interruption of stress granule dynamics (8) and chronic UPR activation (2). The UPR appears to be different in young and aged tau transgenic mice, consistent with a number of other studies showing that the UPR changes with age (9). Moreover, while the UPR can lead to cell death under certain conditions, it is also a necessary cascade that can have protective effects (9). We will evaluate how tau and the aging neuronal environment converge to regulate proteotoxicity through the UPR cascade. Specifically, we will evaluate the specificity of UPR activation by tau in the aging brain. We also will determine whether inhibition of the UPR protects neurons from tau toxicity through the use of AAV vectors encoding the 3 distinct branches of the UPR. Lastly, we will determine the mechanism through which tau inhibits ERAD and triggers the UPR, paying particular attention to the valosin-containing protein (VCP/p97/cdc48)/Hrd1 ERAD complex. By manipulating the UPR experimentally, we will be able to determine whether some aspects of UPR are beneficial and others detrimental for AD progression.