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  • br Results br Discussion The


    Discussion The present study shows reduced levels of O-GlcNAcylation in several models of AD. Notably, a strong correlation was established between global O-GlcNAcylation levels and some AD-associated pathological features, including hampered mitochondrial bioenergetic function and altered mitochondrial morphology and distribution. Importantly, the pharmacological increase in O-GlcNAcylation levels by Thiamet-G, which inhibits OGA, averted the loss of O-GlcNAcylation levels and cell viability in in vitro models of the disease, reinforcing the idea that targeting this posttranslational modification may constitute a feasible therapeutic intervention to tackle AD pathology. Faulty cerebral glucose metabolism has been pinpointed as a contributing factor underlying the neurodegenerative events that occur in AD [31]. PET studies using 2-fluoro-2-deoxy-glucopyranose (FDG) showed a progressive decline in cerebral glucose metabolism in AD [32,33]. Of note, lessons from clinical and experimental studies revealed that the decline in Glpbio Filipin Complex glucose uptake and metabolism occurs decades before the onset of AD symptoms and histopathological changes suggesting that metabolic deficits occur early in the course of AD [34]. Using post-mortem human brain tissue, we observed a reduction of global O-GlcNAcylation levels in brain tissue from AD subjects, this reduction being more pronounced in brain cortex (Fig. 1), which is in accordance with the observations made by Liu and collaborators [35]. As a plausible explanation, these authors attributed the reduction in O-GlcNAcylation to reduced neuronal glucose availability due to down-regulation of glucose transporters (GLUT) 1 and GLUT3 in the AD brain [36]. A recent study shows that the activation of calpain 1 causes GLUT3 proteolysis and downregulation of O-GlcNAcylation in AD brains [34]. In contrast, Förster and collaborators detected augmented cytosolic O-GlcNAc levels in brain tissue from AD subjects [37]. Those conflicting observations may be the result Glpbio Filipin Complex of the analyses of different post mortem brain tissue regions at different stages of the disease conjugated with different analysis methods as well as the use of different anti-O-GlcNAc antibodies. Furthermore, O-GlcNAcylation levels fluctuate depending on the post mortem interval [38] and stage of the disease. Additionally, we observed an increase in global O-GlcNAcylation levels in brain tissue from mature mice, an effect more pronounced in brain cortex from WT mice (Fig. 2). In fact, it is known that age alters brain glucose metabolism [39] modulating O-GlcNAcylation levels. In accordance with our observations, Fülöp et al. [40] observed an increase in the levels of this posttranslational modification in the brain of aged Brown-Norway rats. However, other studies revealed a decrease in O-GlcNAcylation levels in aged mice [41,42] rendering the brain more prone to dysfunction under stress conditions such as brain ischemia. However, those studies used 22–24-month-old WT mice while in our study we used younger (11–12-month old) mice. In our study, 11–12-month-old 3xTg-AD mice show a reduction in brain O-GlcNAcylation levels, an effect more pronounced in brain cortex (Fig. 2). Accordingly, a recent study performed in 12-month-old 3xTg-AD mice shows a decrease of total O-GlcNAcylation levels associated with altered OGT and OGA activation [43]. Proteomics analysis identified several proteins with reduced O-GlcNAcylation levels, which belong to key pathways involved in the AD progression such as neuronal structure, protein degradation and glucose metabolism [43]. In accordance the proteomic quantitative analysis performed by Wang and colleagues [44] revealed that post mortem AD brain tissue presents altered O-GlcNAcylated proteins belonging to several structural and functional categories such as synaptic, cytoskeleton and memory-associated proteins. Besides that, altered O-GlcNAcylation cycling might result in abnormal O-GlcNAcylated tau and APP contributing to the accumulation of toxic species in the brain supporting the idea that impaired O-GlcNAcylation levels contribute to the progression of AD [34].