Among the putative mechanisms involved in Down syndrome (DS) neurodegeneration, the reduction of cerebral glucose metabolism could be highly relevant by impacting the hexosamine biosynthetic pathway (HBP).
As reported in Alzheimer disease (AD), defective HBP leads to flawed protein O-GlcNAcylation coupled by a mutual increase of protein phosphorylation on Ser/Thr residues. This mutual relationship, gives to reduced O-GlcNAc the burden to affect several pathways crucial in the neurodegenerative process.Defects in glycosylation of APP and Tau have been extensively discuss in AD.
Our work aimed to unravel, for the first time, the role of reduced glucose metabolism and of aberrant protein O-GlcNAcylation in DS neuropathology.
We will investigate global O-GlcNAc/Ser/Thr phosphorylation ratio on the hippocampus of Ts2Cje (Ts2), mouse model of DS, at different ages. In parallel, we will analyse the relationship between altered O-GlcNAc levels, the activity of OGT and OGA enzymes (involved in O-GlcNAcylation cycling) and the O GlcNAcylation/phosphorylation ratio of APP and tau AD-related toxic products. At the end a glyco- proteomics approach, we will help to identify aberrantly O-glycosylated proteins to investigate novel molecular mechanism which may contribute to neurodegeneration in DS neuropathology.
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 50ys, 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 to unravel 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 four aims 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. Deepening the knowledge of such pathogenic mechanisms could allow to identify novel druggable targets.
The characterization of the exact pathogenic pathways involved in the development of these conditions might help to understand how specific nutrients and dietary patterns impact on functional decline of specific organs, and it could pave the way to developing relatively simple nutritional strategies (or drug therapies) to counteract or delay the onset of metabolic and functional alterations characteristic of ageing.