Metabolic responses to O-GlcNAcase inhibition in APPNL-G-F mice

Antibodies against β-amyloid (Aβ) show promise in the treatment of Alzheimer’s disease (AD), creating opportunities for combination therapies. Protein O-GlcNAcylation is altered in human AD and animal models, but clinical O-GlcNAcase (OGA) inhibition has reduced p-tau without providing cognitive benefit and has produced adverse effects. Here, we examined O-GlcNAcylation and metabolic responses in the App NL-G-F knock-in AD mouse model. We found overall elevated protein O-GlcNAc levels in App NL-G-F mice compared to C57BL/6J wildtype (WT) mice. Administration of Thiamet G (35 mg/kg, i.p., twice weekly for 10 weeks) elevated OGA activities in App NL-G-F mice, as previously reported in WT mice. Both WT and App NL-G-F mice exhibited even higher O-GlcNAcylation after Thiamet G treatment, but no significant changes were observed in overall Aβ plaque loads, GFAP, or IBA1 levels. Cytosolic metabolic enzyme lactate dehydrogenase (LDH) activities were decreased in App NL-G-F males compared to WT male mice in both saline and TG treated groups. Mitochondrial complex I activities were increased in App NL-G-F male compared to WT mice and decreased to WT level by Thiamet G. High-resolution metabolomics in female mice showed changes in TCA cycle, fatty acid oxidation, and nucleotide sugar pathways, consistent with altered glycolysis and mitochondrial networks with elevated protein O-GlcNAcylation in WT mice. Metabolic differences between WT and App NL-G-F mice involved N-glycan, branched-chain amino acids and nicotinate/nicotinamide metabolism and were more pronounced following elevated protein O-GlcNAcylation. Elevation of protein O-GlcNAcylation in App NL-G-F mice induced alterations in metabolites within the histidine pathway and carnitine shuttle, indicating O-GlcNAc-sensitive remodeling of AD-relevant metabolic networks. Taken together, this study shows that enhanced protein O-GlcNAcylation in APP NL-G-F knock-in AD mice is associated with altered glycan and energy-related pathways relevant to mechanisms of AD metabolic dysfunction.