PROJECT SUMMARY At the heart of Alzheimer’s (AD) pathogenesis, tau pathology is linked to neurodegeneration and cognitive decline. We have spent the last decade addressing how tau exerts its toxicity in AD. Among the many tau post- translational modifications (PTMs) that are now known to co-occur and target tau, acetylation of tau’s lysines, which have emerged from recent cryo-EM and mass spectrometry studies, is a particularly relevant and attractive target. Coupled with the fact that acetylation accelerates tau aggregation, prevents normal microtubule binding, and induces prominent AD-like deficits including synaptic dysfunction and cognitive decline, these properties would appear to set this particular PTM apart from many of the other tau PTMs that are known to regulate tau. While acetylated tau is common to virtually all sporadic AD brains, there remain few reliable models to unravel the signaling events and enzymes that converge on this idea. In our view, this gap needs to be overcome if we hope to unravel mechanisms that drive tau pathogenesis. We identified a new signaling pathway in which the Parkinson’s disease (PD)-relevant kinase LRRK2 acts upstream to regulate HDACs and therefore indirectly controls tau acetylation. We hypothesize that LRRK2 and other related “HDAC kinases” act as master regulators of HDAC function, with their end goal of preventing the accumulation of acetylated tau and thereby protecting against tau toxicity. In Aim-1, we develop a new model based on an engineered cytoplasmic CBP acetyltransferase to precisely target cytoplasmic tau and then assess the extent of tau pathology, synaptic dysfunction, tau seeding, and tau propagation. Having narrowed in on HDACs 3/6 as the only tau-associated HDACs among all human HDACs, we will deliver them to neurons and determine whether synergism among HDACs converges onto tau to suppress its toxicity. In Aim-2, we focus on the upstream kinases that coordinate HDAC activity. We explore LRRK2 as a very attractive hit identified in a mini screen that modulates HDAC3/6 function. We will manipulate LRRK2 function in mouse neurons, mice, and human iPSC neurons to evaluate downstream consequences on HDACs and tau. Our proposal will shed light, not only on AD-relevant HDACs, but also open up new therapeutic avenues (e.g., the targeting of upstream kinases) to suppress toxic tau species in the brain. This proposal is therefore both innovative and significant since upstream HDAC regulatory kinases including LRRK2 and PKC hold promise as unanticipated regulators of HDAC activity. This will expand our repertoire of targetable pathways in tauopathies that include AD and even PD as well.