Investigating the effects of increasing O-GlcNAcylation in Alzheimer's disease

PROJECT SUMMARY/ABSTRACT Alzheimer's disease is a devastating neurodegenerative disease with limited therapeutic options. Progressive accumulation of the pathological markers, hyperphosphorylated Tau (pTau), amyloid-beta, and gliosis begin up to 20 years before cognitive impairment occurs. Published reports from our lab and others have shown that the TgF344-AD rat model displays many of the early pathological abnormalities that occur in patients with AD, including endogenous pTau accumulation in the locus coeruleus prior to other brain regions, Aβ accumulation throughout hippocampus, degeneration of noradrenergic (NA) axons in hippocampus, reactive astrocytes and microglia, as well as a synaptic dysfunction as early as 6 months in the dentate gyrus. Therapeutic strategies that interfere with these pathological changes could slow disease progression. Increasing the post- translational modification, O-GlcNAcylation, has received recent attention, as it competes with serine/threonine phosphorylation on Tau, preventing its hyperphosphorylation and accumulation. Increasing O-GlcNAcylation also increases non-amyloidogenic processing of amyloid precursor protein due to O-GlcNAcylation of gamma secretase. Pharmacological inhibitors of O-GlcNAcase, the enzyme that removes O-GlcNAc moieties from proteins, are currently in clinical trials for the treatment of AD in patients. Using the TgF344-AD rat model and a combination of technical approaches including immunohistochemistry, confocal imaging, Western blot and brain slice electrophysiology, my dissertation research focuses on pharmacologically increasing O- GlcNAcylation in TgF344-AD rats to test whether it is therapeutically beneficial by (1) decreasing pathogenic accumulation of pTau and amyloid-β (Aβ), preventing NA axon degeneration, and decreasing astrocyte and microglia activation, (2) prevents the pathologically increased LTP due to β-ARs function at MPP-DG synapses and (3) maintaining astrocyte function, including astrocytic β-ARs.