Dottorato in BIOCHIMICA

Titolo della tesi: Aberrant protein O-GlcNAcylation promotes Alzheimer-like neuropathology

Growing evidences have recently pointed out disturbances of protein O-GlcNAcylation as a possible link between altered brain metabolism and the progression of neurodegenerative processes. As observed in Alzheimer’s disease (AD) brain, flaws of the cerebral glucose uptake translate into reduced HBP flux thus leading to impaired protein O-GlcNAcylation. Notably, the nutrient-related reduction of O-GlcNAcylated proteins triggers an aberrant increase of tau and APP phosphorylation in AD brain, favouring the formation of toxic neurofibrillary tangles and β-amyloid plaques which contribute to disease pathogenesis. Given that Down syndrome (DS) and AD share similar metabolic alterations and common pathological markers within the brain, it is conceivable to suppose a role for aberrant O-GlcNAcylation in driving DS neurodegeneration. The first part of this work aimed to evaluate possible alterations occurring in the O-GlcNAc homeostasis and its implications in mediating the progression of AD-like dementia in a murine model of DS (Ts2Cje). In this context, a wide range of studies have recently emphasized the use of O-GlcNAc-modulating compounds as a novel target to counteract neurodegeneration. In accordance, the brain-targeted OGA inhibition strategy that we have tested might represent a valuable therapeutic strategy to ameliorate AD-like neurodegeneration in DS subjects by the recovery of global and specific O-GlcNAcylation of AD-hallmarks and through the induction of autophagy. Several evidences suggest that diabetes and defects in glucose metabolism might predispose to poorer cognitive performances and dementia during ageing. On to the other hand, hypercaloric diets demonstrated to affect cognitive performances promoting metabolic dysregulation in the brain. In this scenario, the ability of protein O-GlcNAcylation to relate cellular metabolic status to well-known aspects of AD-like neurodegeneration challenged us to investigate the contribution of metabolic-induced changes in protein O-GlcNAcylation of a murine model of diet-induced neurodegeneration (HFD), with the aim of discerning common and divergent aspects with DS-related neurodegeneration. According to the second part of our study, reduced HBP flux, impaired O-GlcNAcylation and defective insulin signalling appear to cooperate in the progression of the neurodegenerative process of HFD mice, eventually resulting in mitochondrial defects, reduced energy consumption and in the development of typical AD signatures.