Alzheimers disease-related pathology and impaired cognitive function associate with reduced O-GLCNAC transferase in aged metabolic syndrome KKAY(+/-) mice

Alzheimers disease-related pathology and impaired cognitive function associate with reduced O-GLCNAC transferase in aged metabolic syndrome KKAY(+/-) mice

Jinka S;Lallo Jason;Gupta S;Mathias A;Khanal S;Al-Rhayyel Y;Herman D;Fleming S;Raman P

Faseb Journal

2020

2020-04

Metabolic syndrome (MetS) refers to a cluster of anomalies including type 2 diabetes, obesity, insulin resistance and dyslipidemia. Patients with MetS are 1.5 times more likely to develop late‐onset Alzheimer’s Disease (AD), with impaired glucose metabolism, defective insulin signaling, increased oxidative stress and inflammation being shared between the comorbid diseases. Notably, risk of AD is profoundly enhanced in the aging MetS population. Recent studies in AD patients and AD mouse models suggest a putative link between hyperphosphorylated tau neurofibrillary tangles, a commonly accepted AD pathology, and cerebral glucose hypometabolism. Impaired glucose metabolism is characterized by reduced glucose flux through the hexosamine metabolic pathway triggering attenuated signaling via O‐linked N‐acetylglucosamine (O‐GlcNAc) transferase (OGT), a major regulator of intracellular protein O‐GlcNAcylation. However, the role of OGT in the etiology of MetS‐induced AD remains incompletely understood. The goal of the present study was to examine the link between cognitive function, AD pathology and OGT signaling in a mouse model of MetS (KKAy+/−) that develops increased body weight, hyperglycemia, elevated total cholesterol and total triglyceride levels. Briefly, male and female obese agouti KKAy+/−, lean non‐agouti KKAy−/− and normal C57BL/6 control mice weaned at 4 wks of age on regular chow diet were subjected to periodic body weight and random blood glucose monitoring followed by a battery of behavioral tests at 12+ months of age. Plasma and brain (frontal cortex and hippocampus) tissues were then harvested from each genotype for biochemical and molecular studies. In an object recognition test of attention and memory, obese KKAy+/− mice showed a more severe impairment in discrimination between a novel and familiar object compared to lean KKAy−/− and normal C57BL/6 mice. Additionally, in a test of spontaneous activity obese KKAy+/− mice made significantly fewer rears vs lean KKAy−/− mice and wild‐type C57BL/6 controls; these results suggest diminished cognitive function in the obese KKAy+/− mice. Furthermore, immunoblotting of brain tissue lysates derived from the agouti KKAy+/− mice revealed increased ptau expression coupled with reduced pERK (signaling mediator of neuronal function) and pGSK (inactive form of tau kinase GSK3β) expression compared to non‐agouti KKAy−/−. Importantly, augmented tau phosphorylation was concomitant to attenuated OGT expression in brain lysates of obese KKAy+/− mice. Together, these data demonstrate a direct association between cognitive dysfunction, AD‐related pathology and reduced OGT expression in aged MetS KKAy+/− mice. Overall, our study implicates a role of OGT in MetS‐induced cognitive decline and AD pathogenesis.

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