ABSTRACT
BACKGROUND: Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer's disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice. OBJECTIVE: Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). METHODS: STZ was injected into the lateral ventricle of C57BL/6J mice. From the second day, Thiamme2-G (TM2G) or saline, as a vehicle control, was orally administered to the ICV-STZ mice three times per week for five weeks. A separate group of ICV-saline mice treated with saline was used as a baseline control. Behavioral tests, including open field and novel object recognition, were conducted three weeks after the first dose of the TM2G or saline. Protein O-GlcNAcylation, tau hyperphosphorylation, synaptic proteins, and neuroinflammation in the mouse brain were assessed by western blotting. RESULTS: ICV-STZ caused decreased protein O-GlcNAcylation. Enhancement of O-GlcNAcylation to moderate levels by using low-dose OGA inhibitor in ICV-STZ mice prevented STZ-induced body weight loss, rescued cognitive impairments, and restored AD-like pathologies, including hyperphosphorylation of tau and abnormalities in synaptic proteins and neuroinflammation. CONCLUSION: These findings suggest that moderately increasing protein O-GlcNAcylation by using low doses of OGA inhibitor may be a suitable therapeutic strategy for sAD.
Subject(s)
Cognitive Dysfunction/drug therapy , Enzyme Inhibitors/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors , tau Proteins/metabolism , Animals , Brain/drug effects , Brain/metabolism , Cognition/physiology , Cognitive Dysfunction/metabolism , Disease Models, Animal , Enzyme Inhibitors/therapeutic use , Mice , Phosphorylation/drug effects , Recognition, Psychology/physiologyABSTRACT
The synthesis of analogues of the potent N-acetylhexosaminidase inhibitor, PUGNAc, are described. These compounds were assayed against a set of biologically important N-acetyl-d-glucosaminidases and were found to vary in both potency and selectivity.
Subject(s)
Enzyme Inhibitors/pharmacology , Phenylcarbamates/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Conformation , Phenylcarbamates/chemical synthesis , Phenylcarbamates/chemistry , Structure-Activity Relationship , beta-N-Acetylhexosaminidases/metabolismABSTRACT
Pyrrolidine-based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O-GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O-GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O-GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.
