Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice

Article type: Research Article

Authors: Pan, Danmin^{a; 1} | Gu, Jin-Hua^{a; 2} | Zhang, Jin^{a; 3} | Hu, Yae^{a; 4} | Liu, Fei^a | Iqbal, Khalid^a | Cekic, Nevena^b | Vocadlo, David J.^{b; c} | Dai, Chun-Ling^{a; *} | Gong, Cheng-Xin^{a; *}

Affiliations: [a] Department of Neurochemistry, Inge Grundke-Iqbal Research Floor New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA | [b] Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada | [c] Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada

Correspondence: [*] Correspondence to: Cheng-Xin Gong and Chun-Ling Dai, Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Tel.: +1 718 494 5248; Fax: +1 718 494 1080; E-mail: [email protected] (Cheng-Xin Gong) or [email protected] (Chun-Ling Dai).

Note: [1] Present address: School of Life Science, Nantong University, Nantong, Jiangsu, China.

Note: [2] Present address: Department of Clinical Pharmacy, Affiliated Maternity & Child Health Care Hospital of Nantong University, Nantong, Jiangsu, China.

Note: [3] Present address: Department of Rehabilitation, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.

Note: [4] Present address: Department of Pathophysiology, Medical School of Nantong University, Nantong, Jiangsu, China.

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.

Keywords: Alzheimer’s disease, O-GlcNAcylation, OGA, OGA inhibitor, tau hyperphosphorylation, Thiamme2-G

DOI: 10.3233/JAD-201450

Journal: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 273-286, 2021