PROJECT SUMMARY Alzheimer's disease is a progressive, irreversible neurological disorder that slowly destroys the ability to live independently by affecting memory and thinking skills. While few treatments currently help with some symptoms, no interventions have yet been demonstrated to delay the onset or slow the progression. Alzheimer's symptoms are caused by loss of neurons and synapses in the cerebral cortex and subcortical regions, zones where two neuropathological signs have been found: neurofibrillary tangles and Amyloid plaques. Neurofibrillary tangles and amyloid plaques are toxic protein aggregates mainly composed respectively by hyperphosphorylated Tau and amyloid fragment Aβ that cause cell death and neurodegeneration. One of the keys to reduce the neurodegeneration happening in Alzheimer's patients is to prevent or block the formation of these aggregates. NMNAT is an endogenous enzyme involved in cellular metabolism that is known for its neuroprotective functions, in particular in axon degeneration. Recently, it has been shown that NMNAT can protect cells from protein-aggregates-induced neurotoxic stress by acting as a chaperone. Chaperones are endogenous proteins responsible for the re-folding or degradation of misfolded proteins. The long term goal of this project is to investigate if NMNAT neuroprotective activity can be used in the treatment of Alzheimer's disease. The objective of this proposal is to determine if overexpression of NMNAT in two different animal models of Alzheimer's disease can delay or prevent the formation of neurofibrillary tangles and amyloid plaques. The central hypothesis of this study is that NMNAT chaperone activity is conserved throughout species and that it can be used in the proteinopathy aspect of Alzheimer's. Guided by promising data that showed NMNAT preventing the neurodegeneration caused by Tau in a drosophila model, our central hypothesis will be tested by pursuing two specific aims: (1) Determine if NMNAT has neuroprotective activity in Drosophila models of Alzheimer's Disease and (2) Determine if NMNAT has neuroprotective activity in a mouse model of Alzheimer's Disease. The rationale for the proposed research is that the results will make a lasting impact in the understanding of neuroprotective pathways that can lead to the treatment of Alzheimer's disease. The proposed research is therefore relevant to the mission of the NIA “to support and conduct genetic, biological, clinical, behavioral, social, and economic research related to the aging process, diseases and conditions associated with aging” and to the current priority of NIA to “Improve our understanding of Alzheimer's disease, other dementias of aging, and the aging brain”.