RT Journal Article SR Electronic T1 MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 252 OP 263 DO 10.1124/jpet.120.266122 VO 374 IS 2 A1 Xiaohai Wang A1 Wenping Li A1 Jacob Marcus A1 Michelle Pearson A1 Lixin Song A1 Karen Smith A1 Giuseppe Terracina A1 Julie Lee A1 Kwok-Lam Karen Hong A1 Sherry X. Lu A1 Lynn Hyde A1 Shu-Cheng Chen A1 David Kinsley A1 Jerry P. Melchor A1 Daniel J. Rubins A1 Xiangjun Meng A1 Eric Hostetler A1 Cyrille Sur A1 Lili Zhang A1 Joel B. Schachter A1 J. Fred Hess A1 Harold G. Selnick A1 David J. Vocadlo A1 Ernest J. McEachern A1 Jason M. Uslaner A1 Joseph L. Duffy A1 Sean M. Smith YR 2020 UL http://jpet.aspetjournals.org/content/374/2/252.abstract AB Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo.SIGNIFICANCE STATEMENT MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.