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.
AD is the most common cause of dementia in the world and despite years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Others factors, including impairment in energy metabolism, increased oxidative stress, inflammation, glucose hypometabolism, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Recently, evidences of a tight correlation between neurodegenerative and metabolic diseases has emerged. Intriguingly, the majority of DS individuals will develop AD by the age of 50 years, therefore DS may be considered a human prodromal AD model to study the molecular mechanisms involved in the progression to AD. Thus, in the last decade, growing studies have been focused in unravelling both common and divergent pathways linking DS to AD neurodegeneration. Cognitive declines, including AD-like dementia in DS population, have a big impact on both cost of healthcare and the quality of life. Recently, the evidence of a strong contribute of brain dys-metabolism has emerged in the development of neurodegenerative diseases.
With this proposal and trough the completion of the aims of the project we would be able to identify a novel mechanism, which links brain glucose hypometabolism and AD-like cognitive decline in DS neuropathology. Indeed, the novel hypothesis underlying this project is that reduced glucose uptake in the brain could lead, through altered protein O-GlcNAcylation to age-related cognitive decline. Brain dys-metabolism can be considered a strong risk factor for the cognitive deterioration and, in particular, it may represent a novel target to slow or delay the age- and diet- related cognitive decline.
Overall the brain-targeted rescue of protein O-GlcNAcylation may represent a valuable therapeutic strategy to ameliorate the early development of AD-like pathology in DS subjects.