PROJECT SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia, characterized by misfolding and aggregation of specific proteins which manifest in pathological features including neuronal loss, cognitive decline and histopathological hallmarks such as the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Amyloid plaques comprise extracellular deposits of amyloid-b (Ab) aggregates, where Aβ oligomers are thought to be proteotoxic to neuronal function. Numerous studies have demonstrated that AD-associated proteotoxicity triggers an adaptive unfolded protein response (UPR) which attempts to restore proteostatic dysfunction due to accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR signaling is mediated through PERK/eIF2a, IRE1/XBP1, and ATF6 sensor pathways; relative contributions of these signaling arms to neurodegeneration is complex as they have dual roles in mediating cell survival and cell death. Elevations in PERK/phosphorylated eIF2a, XBP1 mRNA splicing, and increased levels of ER chaperones such as BiP/GRP78, GRP94 and PDI in human AD brain strongly suggests chronic activation of ER stress is evident in human AD pathology. Further, a polymorphism previously linked to bipolar disorders within the XBP1 promoter region was linked to increased AD risk in Chinese populations. Although it has been established that UPR pathways are activated in disorders such as AD, it is not clear whether UPR pathways confer neuroprotective effects, or if their activation can contribute to pathogenesis. Potential neuroprotective effects of the ATF6 pathway in neurodegeneration have remained particularly elusive. ATF6 functions as an ER stress sensor and transcription factor that promotes expression of genes that enhance proper protein folding via increased production of ER chaperones and increased degradation of misfolded proteins. We present new evidence that ATF6 is essential for synaptic function, as Atf6-/- mice display cognitive and behavioral defects associated with reduced synaptic spine density. Further, exogenous expression of the active ATF6 form suppressed accumulation of amyloid fibrils in a murine model of AD. These results provide strong evidence that ATF6 activation may have a physiological role in synaptic activity and cognitive behavior, and acute ATF6 activation can confer neuroprotective effects with AD-associated proteotoxicity. In the proposed study, our efforts will be focused on elucidating potential neuroprotective effects of ATF6 on neuronal and synaptic function, and differentiate potential roles for ATF6 in neurons and microglia. Given the effects of ATF6 on attenuating Aβ plaque formation, we will characterize proteins that are particularly susceptible to proteostatic dysfunction in AD. We will also characterize the effects of ATF6 mutational variants identified in human Achromatopsia patients on neuronal function, and determine whether pharmacological activation of ATF6 is p...