Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy

• Published in: Neuropharmacology Vol. 79; pp. 307 - 313
• Main Authors: Graham, Danielle L., Gray, Audrey J., Joyce, John A., Yu, Dongzi, O'Moore, Jill, Carlson, George A., Shearman, Mark S., Dellovade, Tammy L., Hering, Heike
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2014
• Subjects: Acetylglucosamine - antagonists & inhibitors; Acetylglucosamine - metabolism; Alzheimer's Disease; Animals; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - metabolism; CA1 Region, Hippocampal - pathology; CA3 Region, Hippocampal - drug effects; CA3 Region, Hippocampal - metabolism; CA3 Region, Hippocampal - pathology; Disease Models, Animal; Female; Glycosylation; Male; Mice; Mice, Transgenic; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; O-GlcNAc; O-tau(S400) antibody; OGA; Phosphorylation - drug effects; Pyrans - pharmacology; rTg4510; Tau aggregation; tau Proteins - antagonists & inhibitors; tau Proteins - metabolism; Tauopathies - drug therapy; Tauopathies - metabolism; Tauopathies - pathology; ThiametG; Thiazoles - pharmacology; rTg4510; Alzheimer's Disease; ThiametG; O-tau(S400) antibody; OGA; O-GlcNAc; Tau aggregation
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.11.025

Neurofibrillary tangles (NFT), mainly consisting of fibrillar aggregates of hyperphosphorylated tau, are a defining pathological feature of Alzheimer's Disease and other tauopathies. Progressive accumulation of tau into NFT is considered to be a toxic cellular event causing neurodegeneration. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification and O-GlcNAcylation of tau has been suggested to regulate tau phosphorylation. We tested if an increase in tau O-GlcNAcylation affected tau phosphorylation and aggregation in the rTg4510 tau transgenic mouse model. Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau. This indicates that O-GlcNAcylation prevents the aggregation of tau in a manner that does not affect its normal phosphorylation state. Collectively, our results support O-GlcNAcase inhibition as a potential therapeutic strategy for the treatment of Alzheimer's Disease and other tauopathies. •Acute OGA inhibition transiently reduced tau phosphorylation in rTg4510 mice.•Chronic OGA inhibition protected against tau aggregation in rTg4510 mice.•Chronic OGA inhibition did not affect normal tau phosphorylation in rTg4510 mice.