Ricerc@Sapienza

Disturbances of protein O-GlcNAcylation have pointed out as a possible link between altered brain metabolism and cognitive decline. As observed in Alzheimer disease (AD), flaws of the cerebral glucose uptake translate into reduced HBP flux thus leading to impaired protein O-GlcNAcylation. Notably, the reduction of O-GlcNAcylated proteins triggers the aberrant increase of tau and APP phosphorylation favoring, in AD brain, the formation of toxic aggregates that translate into neurofibrillary tangles and ß-amyloid plaques. Given that Down syndrome (DS) and AD brains share similar metabolic alterations and common pathological markers, it is conceivable to suppose a role for aberrant O-GlcNAcylation in driving DS neurodegeneration. Studies from our laboratory demonstrated the disruption of O-GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and confirm the relevance of O-GlcNAcylation in the appearance of AD hallmarks in the brain of a murine model of DS and AD. Furthermore, we provide evidence for the neuroprotective effects of brain-targeted OGA inhibition. Indeed, the rescue of OGA activity was able to restore protein O-GlcNAcylation, and reduce AD-related hallmarks and decreased protein nitration, possibly as effect of induced autophagy. Based on these findings, the neuroprotective effects of the OGA inhibitor, thiamet G, will be evaluated in DS mice by analyzing mice performances through behavioral tests. In addition, by proteomics approaches, we will search for brain proteins whose O-GlcNAcylation levels might result significantly modulated by the treatment, thus discovering specific pharmacological targets of thiamet G. In summary, our work emphasizes the central role of altered protein O-GlcNAcylation in DS neuropathology and lays the foundations to consider the rescue of protein O-GlcNAcylation as a valuable therapeutic strategy to reduce the alterations of brain metabolism and the development of AD-hallmarks.