Basic Science and Pathogenesis.

Background: Disturbances of protein O-GlcNAcylation have pointed out as a possible link between altered brain metabolism and cognitive decline. We previously demonstrated the disruption of O-GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and we confirmed the relevance of O-GlcNAcylation in the appearance of Alzheimer disease hallmarks in the brain of a murine model of Down syndrome (DS). Furthermore, we provide evidence for the neuroprotective effects of brain-targeted OGA inhibition (Thiamet G). The primary objective of this study is to provide evidence for the neuroprotective effects of brain-targeted OGA inhibition (Thiamet G) by analyzing mice cognition and molecular pathways associated with Alzheimer-like neurodegenenration.

Method: The neuroprotective effects of Thiamet G was evaluated in DS mice by analyzing mice performances in the novel object recognition and Y maze tests. Furthermore we analyzed by immunochemical methods APP and tau modification, and by proteomic approach using ESI-MS/MS technique, we identified brain proteins whose O-GlcNAcylation levels resulted significantly modulated by the treatment.

Result: Data supported the beneficial effect Thiamet G in DS mice hippocampus. The rescue of OGA activity was able to restore protein O-GlcNAcylation, rescue cognitive impairments and reduce AD-related hallmarks. In particular, the recovery of O-GlcNAcylation was associated with the modulation of protein specific O-GlcNAc levels occurring to several components of neuronal architecture, stress response mechanisms and energy production.

Conclusion: 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.