Background: The abnormal hyperphosphorylation of the microtubule-associated protein tau plays a crucial role in neurodegeneration in Alzheimer’s disease (AD) and aggregation of hyperphosphorylated tau into neurofibrillary tangles is a hallmark brain lesion in AD. Besides kinases and phosphatases tau phosphorylation is regulated by O-GlcNAcylation, a posttranslational modification of proteins on the serine or threonine residues with β-N-acetylglucosamine (GlcNAc). O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase, the enzyme catalyzing the transfer of GlcNAc to proteins, and N-acetylglucosaminidase (OGA), the enzyme catalyzing the removal of GlcNAc from proteins. Thiamet-G is a specific and brain permeable OGA inhibitor.
Methods: Analysis of tau pathology and behaviour in rTg4510 mice which are overexpressing an inducible human mutant tau P301L selectively in the forebrain after acute and chronic Thiamet-G administration by the drinking water.
Results: rTg4510 displayed age-dependent progression of tau pathology with tau hyperphosphorylation at AD-relevant epitopes, accumulation of the 64 kDa tau species, and neurofibrillary tangles in cortex and hippocampus. A subset of rTg4510 mice displayed a hyperactive phenotype both in a novel environment and during the diurnal cycle in the home cage, reminiscent of agitated behaviour. The percentage of hyperactive rTg4510 mice increased with age and was prevented by suppression of tau transgene indicating that this phenotype correlates with the progressive tau pathology. Treatment of rTg4510 mice with Thiamet-G increased overall O-GlcNAcylation levels in the brain indicative for sufficient target engagement. Further, Thiamet-G increased O-GlcNAcylation levels on mutant tau isolated from rTg4510 brains. Chronic Thiamet-G treatment significantly reduced soluble and insoluble 64 kDa hyperphosphorylated tau levels and reduced the number of hyperactive rTg4510 animals.
Conclusions: These results support OGA inhibition by Thiamet-G as possible treatment concept to reduce tau pathology and dysfunction.