Contents lists available at ScienceDirect Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr Review O-GlcNAcylation and neuronal energy status: Implications for Alzheimer’s disease Tiffany S. Pinho a,1 , Diogo M. Verde a,1 , Sónia C. Correia a , Susana M. Cardoso a , Paula I. Moreira a,b, ⁎ a CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal b Laboratory of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal ARTICLE INFO Keywords: Alzheimer’s disease Aβ Brain glucose metabolism O-GlcNAc O-GlcNAcylation Tau ABSTRACT Since the first clinical case reported more than 100 years ago, it has been a long and winding road to demystify the initial pathological events underling the onset of Alzheimer’s disease (AD). Fortunately, advanced imaging techniques extended the knowledge regarding AD origin, being well accepted that a decline in brain glucose metabolism occurs during the prodromal phases of AD and is aggravated with the progression of the disease. In this sense, in the last decades, the post-translational modification O-linked β-N-acetylglucosaminylation (O- GlcNAcylation) has emerged as a potential causative link between hampered brain glucose metabolism and AD pathology. This is not surprising taking into account that this dynamic post-translational modification acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. Within this scenario, the present review aims to summarize the current understanding on the role of O-GlcNAcylation in neuronal physiology and AD pathology, emphasizing the close association of this post-translational modification with the emergence of AD-related hallmarks and its potential as a therapeutic target. 1. Introduction At the beginning of this century the sequencing of the human genome represented one of the most important achievements in the history of science. Strikingly, this study revealed that the human genome only comprises less than 40,000 genes, of which 20–25,000 genes are responsible for coding proteins (International Human Genome Sequencing, 2004). Taking into consideration the complex mechanisms of the cells, the number of genes was expected to be higher. However, the high diversity of cellular machinery, compared to the low number of coding genes, may be in part explained by the presence of numerous post-translational modifications, such as phos- phorylation, glycosylation, sumoylation, acetylation, ubiquitination, nitrosylation, among many others, that will determine protein activity, localization, and their interaction with other proteins (Issad et al., 2010). Among those post-translational modifications, glycosylation and phosphorylation are by far the most abundant and studied, and whereas phosphorylation is usually rapid and reversible allowing cells to re- spond quickly to different stimuli, glycosylation is considered a stable modification that involves the addition of complex carbohydrate chains to proteins and lipids (Issad et al., 2010; Lefebvre et al., 2010). Speci- fically, glycosylation can occur in Serine (Ser) and Threonine (Thr) (O- glycosylation) or Asparagine (Asn) (N-glycosylation) residues, and are restricted to specific cells compartments such as the endoplasmic re- ticulum (ER), Golgi apparatus and extracellular surface of the plasma membrane (Issad et al., 2010). However, back in 1984, a study in T- lymphocytes with exogenous bovine β-1,4- galactosyltransferase en- abled researchers to discover a new type of glycosylation: the O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) (Hanover et al., 1987; Torres and Hart, 1984), which consists in the post-translational addi- tion of a single monosaccharide N-acetylglucosamine on the hydroxyl https://doi.org/10.1016/j.arr.2018.05.003 Received 3 March 2018; Received in revised form 3 April 2018; Accepted 14 May 2018 ⁎ Corresponding author at: Laboratory of Physiology, Faculty of Medicine, University of Coimbra & Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. 1 These authors contributed equally to this work. E-mail addresses: venta@ci.uc.pt, pimoreira@fmed.uc.pt (P.I. Moreira). Abbreviations: 3xTg-AD, triple transgenic mouse model of Alzheimer’s disease; AD, Alzheimer’s disease; AMPK, AMP-activated protein kinase; Asn, asparagine residue; ATP5A, ATP synthase subunit α;Aβ, amyloid-β peptide; AβPP, amyloid-β precursor protein; ER, endoplasmic reticulum; GFAT, glutamine fructose-6-phosphate amidotransferase; GlcNAcstatin, GlcNAc-configured nagstatin derivative; HAT, histone acetyl transferase; HBP, hexosamine biosynthetic pathway; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; mOGT, mitochondrial O-GlcNAc transferase isoform; NButGT, 1,2-dideoxy-2′-methyl-α-D-glucopyranoso-[2,1-d]-D2′-thiazoline (); ncOGT, nucleocytoplasmic O-GlcNAc transferase isoform; OGA, O-GlcNAcase; OGA-L, long O-GlcNAcase isoform; OGA-S, short O-GlcNAcase isoform; O-GlcNAcylation, O-linked β-N-acetylglucosaminylation; OGT, O-GlcNAc transferase; PUGNAc, O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate; Ser, serine residue; sOGT, short O-GlcNAc transferase isoform; STZ, streptozotocin; Thr, threonine residue; TPR, tetraticopeptide repeat motifs; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine Ageing Research Reviews 46 (2018) 32–41 Available online 19 May 2018 1568-1637/ © 2018 Elsevier B.V. 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