The disturbance of
protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with
Alzheimer's disease (AD), flaws of the cerebral
glucose uptake translate into reduced
protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and
insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related
cognitive decline might be played by aberrant
protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total
protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of
protein O-GlcNAcylation was associated with the development of
insulin resistance, induced by overfeeding (i.e., defective
insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the
hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.