Investigating the neuroprotective role of OGA inhibition by Thiamet-G against Alzheimer\'s disease

The glycosylation of nucleocytoplasmic proteins by O-linked N-acetylglucosamine (O-GlcNAc) is important for regulation of protein function and cellular signaling. Addition of GlcNAc monosaccharide unit to target proteins requires the enzyme O-GlcNAc transferase (OGT), and removal of O-GlcNAc depends on the enzyme O-GlcNAcase (OGA). Previous works have shown that OGA inhibitors and enhancers of autophagy both reduced cognitive impairment as well as Aβ and tau aggregation in Alzheimer\'s disease (AD) mouse models. Here, it was shown that OGA inhibition enhanced autophagy in neuro-2a cells and AD mouse brain through an mTOR independent pathway. These data suggest that OGA inhibition provides neuroprotection by promoting autophagy dependent clearance of protein oligomers. To investigate this relationship, we established inducible cellular models of tauopathy to show that OGA inhibition decreased levels of pathological tau species. These results suggest OGA inhibition is a possible therapeutic strategy against AD that may involve the enhancement of autophagy.