Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice
| Autor: | Fei Liu, Chun-ling Dai, Cheng-Xin Gong, Nevena Cekic, David J. Vocadlo, Khalid Iqbal, Jin-hua Gu, Danmin Pan, Yae Hu, Jin Zhang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Tau protein Hyperphosphorylation tau Proteins Open field Mice 03 medical and health sciences Cognition 0302 clinical medicine Downregulation and upregulation Internal medicine medicine Animals Cognitive Dysfunction Enzyme Inhibitors Phosphorylation Neuroinflammation biology business.industry General Neuroscience Neurodegeneration Brain Recognition Psychology General Medicine medicine.disease Streptozotocin beta-N-Acetylhexosaminidases Blot Disease Models Animal Psychiatry and Mental health Clinical Psychology 030104 developmental biology Endocrinology biology.protein Geriatrics and Gerontology business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Alzheimer's Disease. 81:273-286 |
| ISSN: | 1875-8908 1387-2877 |
| DOI: | 10.3233/jad-201450 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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