Diabetes mellitus aggravates behavioral deficit and increases site-specific phosphorylation of tau protein in alzheimer's disease mouse model.

Objective: Numerous epidemiological studies have demonstrated that vascular risk factors including diabetes mellitus (DM) increase the risk of developing Alzheimer's disease (AD). However, the mechanisms underlying the pathological relationship between DM and AD remain largely unknown. Tau is a microtubule-associated protein that is predominantly expressed in the axons of neurons. More than 80 residues of tau can be potentially phosphorylated. Accumulation of hyperphosphorylated tau protein plays a role in neurodegeneration and cognitive impairment in patients with AD. Here, we developed a unique diabetic AD mouse model and analyzed behavioral phenotypes and biochemical changes occurring in the brain to investigate the impact of DM on tau pathology. Design and method: Tau-tg and WT mice were fed with either normal chow diet (NCD; 12% kcal fat, n = 9) or high-fat diet (HFD; 60% kcal fat, n = 10) from the age of one and a half to nine months. Metabolic parameters and behavioral phenotypes were assessed at eight months of age. Mice were then sacrificed at nine months of age and brains were analyzed histologically and biochemically. A quantitative proteomic analysis of protein phosphorylation was performed using brain extracts of tau-tg mice. Results: Tau-tg mice fed with HFD (HFD tau-tg) showed severe obesity and hyperinsulinemia compared with tau-tg mice fed with NCD (NCD tau-tg) (p < 0.01), with slight elevation of plasma glucose levels. HFD tau-tg showed exacerbation of motor impairments and decrement of habituation to novel environment. Histological analysis showed a significant decrease in the number of neurons in HFD tau-tg compared to NCD tau-tg. The amount of aggregated form of phospho-tau (Ser396) was increased in HFD tau-tg brain. Comprehensive phosphoproteomic analysis identified 11 phosphosites of tau significantly hyperphosphorylated in the brain of HFD tau-tg (p < 0.05). Conclusions: These results suggest that diabetic conditions such as obesity and hyperinsulinemia with minimal hyperglycemia exacerbate behavioral deficits in AD via hyperphosphorylation of tau protein. We identified specific phosphosites of tau involved in pathological relationship between DM and AD.