Cognitive dysfunction and increased phosphorylated tau are associated with reduced O‐GlcNAc signaling in an aging mouse model of metabolic syndrome

Abstract

Metabolic syndrome (MetS), characterized by hyperglycemia, obesity, and hyperlipidemia, can increase the risk of developing late‐onset dementia. Recent studies in patients and mouse models suggest a putative link between hyperphosphorylated tau, a component of Alzheimer's disease‐related dementia (ADRD) pathology, and cerebral glucose hypometabolism. Impaired glucose metabolism reduces glucose flux through the hexosamine metabolic pathway triggering attenuated O‐linked N‐acetylglucosamine (O‐GlcNAc) protein modification. The goal of the current study was to investigate the link between cognitive function, tau pathology, and O‐GlcNAc signaling in an aging mouse model of MetS, agouti KKAy+/−. Male and female C57BL/6, non‐agouti KKAy−/−, and agouti KKAy+/− mice were aged 12–18 months on standard chow diet. Body weight, blood glucose, total cholesterol, and triglyceride were measured to confirm the MetS phenotype. Cognition, sensorimotor function, and emotional reactivity were assessed for each genotype followed by plasma and brain tissue collection for biochemical and molecular analyses. Body weight, blood glucose, total cholesterol, and triglyceride levels were significantly elevated in agouti KKAy+/− mice versus C57BL/6 controls and non‐agouti KKAy−/−. Behaviorally, agouti KKAy+/− revealed impairments in sensorimotor and cognitive function versus age‐matched C57BL/6 and non‐agouti KKAy−/− mice. Immunoblotting demonstrated increased phosphorylated tau accompanied with reduced O‐GlcNAc protein expression in hippocampal‐associated dorsal midbrain of female agouti KKAy+/− versus C57BL/6 control mice. Together, these data demonstrate that impaired cognitive function and AD‐related pathology are associated with reduced O‐GlcNAc signaling in aging MetS KKAy+/− mice. Overall, our study suggests that interaction of tau pathology with O‐GlcNAc signaling may contribute to MetS‐induced cognitive dysfunction in aging.