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.

Giuseppe Terracina,Lili Zhang,Shu‐Cheng Chen ,Joel B. Schachter,Karen D.b. Smith ,Joseph Duffy ,Jerry P. Melchor,J. Fred Hess,Jacob Marcus,Jason M. Uslaner,Daniel Rubins ,Lynn A. Hyde ,Cyrille Sur,Harold G. Selnick,Steve Lu ,David J. Vocadlo,Xiangjun Meng,Julie Lee,Wenping Li,Xiaohai Wang,Kwok-Lam Karen Hong,Sean M. Smith,Eric D. Hostetler ,David Kinsley,Ernest J. McEachern,Michelle Pearson,Lixin Song

doi:10.1124/jpet.120.266122

Giuseppe Terracina, Lili Zhang + Show 25 more

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https://doi.org/10.1124/jpet.120.266122

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Abstract

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.

Highlights

Neurofibrillary tangles (NFTs), a pathologic hallmark of Alzheimer disease (AD), are mainly composed of intracellular hyperphosphorylated and aggregated microtubule-associated protein tau (Lee et al, 2001; Ballatore et al, 2007)
The dynamic cycling of this protein modification is controlled by a single pair of enzymes: O-GlcNAc transferase (OGT), which catalyzes the transfer of a N-acetylglucosamine (GlcNAc) moiety to the target serine and threonine residues, and O-GlcNAcase (OGA), which catalyzes the hydrolysis of this sugar modification (Hart et al, 2007)
The current study provides an extensive characterization of the effects of OGA inhibition on tauopathy in preclinical models by using MK-8719, a highly selective and potent inhibitor of OGA enzyme with similar potency across multiple species

Summary

Introduction

Neurofibrillary tangles (NFTs), a pathologic hallmark of Alzheimer disease (AD), are mainly composed of intracellular hyperphosphorylated and aggregated microtubule-associated protein tau (Lee et al, 2001; Ballatore et al, 2007). In frontotemporal dementia with parkinsonism type-17, tau is causally related to the neurodegeneration and dementia, as demonstrated by the discovery that mutations in the tau gene cause the disease (Hutton et al, 1998) These mutations may affect alternative splicing of tau mRNA, decrease the ability of tau to bind microtubules, and increase the propensity of tau to form aggregates (Dayanandan et al, 1999; Gamblin et al, 2000; Lee et al, 2001). O-GlcNAcylation may be considered as an intracellular sensor of glucose metabolism status (Gong et al, 2016)

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