Project Summary/Abstract Alzheimer’s disease and its related dementias (ADRD) are associated with high rates of neuronal death in affected areas, but little is known about the ability of the brain to recover following therapeutic intervention. ADRD are characterized by protein deposits consisting of beta-Amyloid peptide and microtubule-associated protein tau. Tau pathology develops independently of beta-Amyloid deposits, and removal of beta-Amyloid alone is not sufficient to reduce cognitive decline in mice. The dysfunction of tau is characterized by an abnormal state of hyper-phosphorylation (P-tau), induced via a plethora of kinase pathways. This P-tau disrupts cellular function by sequestering other microtubule-associated proteins, directly destabilizing microtubules, and binding normal tau to form paired helical filaments (PHF-tau). Turnover of the tau protein is decreased in this pathology, as PHF-tau is resistant to neuronal proteases and degradation by ubiquitination. In vitro dephosphorylation of P-tau by the phosphoprotein phosphatase PP2A induces dissociation of PHF-tau and restores susceptibility of tau to protease digestion. PP2A activity and expression is diminished in neurons exhibiting P-tau pathology. Preliminary data from our lab indicate that direct delivery of PP2A DNA to the dorsal raphe nucleus (an early presenter of tau pathology) is sufficient to decrease P-tau in ADRD-model mice. To date, no studies have used targeted reversal of tau pathology at different disease-progression stages to investigate ADRD treatment outcomes. This proposal will investigate the reversal of P-tau pathology in serotonergic neurons, to determine any rescue of function or mitigation of P-tau propagation. These findings will further the understanding of early Alzheimer’s Disease, and may identify a clinically-relevant therapeutic intervention. Additionally, this fellowship training plan gives high priority to the professional development and research training of the fellowship recipient. This research training will take place in a highly collaborative and interdisciplinary laboratory setting within the University of Iowa’s department of Neuroscience and Pharmacology.