2025 年 11 巻 p. 10-18
Background: Diabetes mellitus (DM) is a risk factor for both vascular dementia and Alzheimer’s disease (AD). We previously reported that tau phosphorylation is increased in the brain of a diabetic AD mouse model, which can be an underlying mechanism linking DM and AD. However, the key molecules mediating the tau phosphorylation by DM remain unknown. Here, using a phosphoproteomic approach, we aimed to identify candidate kinases that regulate tau phosphorylation by DM.
Method and Results: We generated diabetic tau-transgenic (TauTg) mice by high-fat diet (HFD) feeding and conducted a phosphoproteomic analysis of their brain tissues. Phosphoproteome profiling of the brains from the diabetic and non-diabetic TauTg mice were compared. We identified 30 kinases whose levels of phosphorylation were significantly altered in the brains of the diabetic TauTg mice. Molecular networking analysis found that six of the 30 kinases were associated with tau phosphorylation. Among the six kinases, the decrease in the phosphorylation levels of CaMK2α, which reflected the severity of diabetic conditions, was associated with the exacerbation of accumulation of phosphorylated tau in the brains of TauTg mice.
Conclusions: Tau-related kinases that potentially mediate DM-induced tau phosphorylation were identified using a phosphoproteomic approach. These kinases could be therapeutic targets for preventing AD in patients with DM.
