PROJECT SUMMARY Tau pathologies including Alzheimer’s disease are the most prevalent and complex neurodegenerative diseases of aging that will likely reach 115 million globally by 2050(6) yet, there are no therapeutic drugs to treat this disease, except a controversial recently approved drug(7). Though the formation of intracellular neurofibrillary tangles (NFTs) from the hyperphosphorylated tau protein in the cortical and hippocampal regions is a key pathological hallmark of tau pathologies, the precise mechanisms of how hyperphosphorylated tau impact survival signaling in neurons is lacking. Recently we have shown that the PI3K/Akt survival signaling pathway is controlled by the non-neuronal type microtubule-associated protein 4 (MAP4) that directly interacts with PI3K via its microtubule-binding domain (MTBD)(9). The PI3K interaction with MAP4 controls the PI3K association with activated receptor kinases that are required for PI3K activation, PI3,4,5P3 generation, and Akt activation(9). The MTBD of MAP4 that binds PI3K shows strikingly high homology with the microtubule- binding domain of the neuronal microtubule-associated proteins tau and MAP2, stimulating the hypothesis that tau and MAP2 substitute for MAP4 control of PI3K/Akt survival signaling in neurons. Our preliminary data shows the association between tau and PI3K in primary neurons, induced pluripotent stem cells-derived neurons, and a neuronal cell line. The siRNA-mediated knockdown of tau blocked insulin stimulated Akt activation. We hypothesize that tau scaffold the PI3K along microtubules in axons and dendrites to control growth factor stimulated PI3K/Akt survival signaling of neurons. Increased tau hyperphosphorylation and its aggregation during Alzheimer’s disease progression impairs the spatial organization of PI3K along microtubules resulting in loss of growth factor stimulated PI3K/Akt signaling that is critical for neuronal cell survival and function. The focus of proposed study is to establish and understand mechanistically tau’s role in the PI3K/Akt signaling and define the PI3K interaction sites in tau. The interaction between PI3K and tau will be used to define the interaction sites for PI3K in the MTBD of tau and investigate if these sites coincide with pathogenic mutants and hyperphosphorylation sites in the MTBD of tau. We will define the effect of tau loss on spatial distribution, co-localization and interaction of PI3K with activated receptors in axons and dendrites, and effect on growth factor stimulated PI3,4,5P3 generation and Akt activation. This will be further substantiated by a systemic investigation of the impact of expressing mutant tau that is deficient on PI3K binding and the disruption of PI3K-tau interaction by cell permeable peptides on spatial PI3K/Akt signaling and survival of neurons.