High-fat diet leads to reduced protein o-glcnacylation and mitochondrial defects promoting the development of alzheimer’s disease signatures

Salvatore Fusco, Claudio Grassi, Francesca Natale, Ilaria Zuliani, Chiara Lanzillotta, Antonella Tramutola, Eugenio Barone, Marzia Perluigi, Serena Rinaldo, Alessio Paone, Francesca Cutruzzolà, Francesco Bellanti, Fabio Di Domenico

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

Abstract

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.
Lingua originaleEnglish
pagine (da-a)N/A-N/A
Numero di pagine25
RivistaInternational Journal of Molecular Sciences
Volume22
DOI
Stato di pubblicazionePubblicato - 2021

Keywords

  • Brain insulin resistance
  • High-fat diet
  • Mitochondria
  • Neurodegeneration
  • Protein O-GlcNAcylation

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