Proteomic identification of altered protein O-GlcNAcylation in a triple transgenic mouse model of Alzheimer's disease

Antonella Tramutola, Nidhi Sharma, Eugenio Barone, Chiara Lanzillotta, Andrea Castellani, Federica Iavarone, Federica Vincenzoni, Massimo Castagnola, D. Allan Butterfield, Silvana Gaetani, Tommaso Cassano, Marzia Perluigi, Fabio Di Domenico

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

PET scan analysis demonstrated the early reduction of cerebral glucose metabolism in Alzheimer disease (AD) patients that can make neurons vulnerable to damage via the alteration of the hexosamine biosynthetic pathway (HBP). Defective HBP leads to flawed protein O-GlcNAcylation coupled, by a mutual inverse relationship, with increased protein phosphorylation on Ser/Thr residues. Altered O-GlcNAcylation of Tau and APP have been reported in AD and is closely related with pathology onset and progression. In addition, type 2 diabetes patients show an altered O-GlcNAcylation/phosphorylation that might represent a link between metabolic defects and AD progression. Our study aimed to decipher the specific protein targets of altered O-GlcNAcylation in brain of 12-month-old 3×Tg-AD mice compared with age-matched non-Tg mice. Hence, we analysed the global O-GlcNAc levels, the levels and activity of OGT and OGA, the enzymes controlling its cycling and protein specific O-GlcNAc levels using a bi-dimensional electrophoresis (2DE) approach. Our data demonstrate the alteration of OGT and OGA activation coupled with the decrease of total O-GlcNAcylation levels. Data from proteomics analysis led to the identification of several proteins with reduced O-GlcNAcylation levels, which belong to key pathways involved in the progression of AD such as neuronal structure, protein degradation and glucose metabolism. In parallel, we analysed the O-GlcNAcylation/phosphorylation ratio of IRS1 and AKT, whose alterations may contribute to insulin resistance and reduced glucose uptake. Our findings may contribute to better understand the role of altered protein O-GlcNAcylation profile in AD, by possibly identifying novel mechanisms of disease progression related to glucose hypometabolism.

Original languageEnglish
Pages (from-to)3309-3321
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number10
DOIs
StatePublished - Oct 2018

Bibliographical note

Publisher Copyright:
© 2018

Keywords

  • Alzheimer disease
  • Glucose metabolism
  • Insulin signaling
  • O-GlcNAcylation
  • Phosphorylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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