High-fat diet-induced changes in tau aggregation activity were associated with hyperphosphorylation at specific phospho-sites

抄録

Background: Diabetes mellitus (DM) has been suggested to increase the risk of developing Alzheimer’s disease (AD). We have previously demonstrated that DM induces a unique phosphorylation pattern in AD-associated tau protein, which correlates with its accumulation in the brain. However, the effect of DM on tau seeding activity was not fully explored. In this study, we quantified tau seeding activity in the brains of diabetic AD mice with a highly sensitive in vitro assay using tau-biosensor cells and investigated its correlation with site-specific tau phosphorylation.

Method and Results: We extracted tau from the brains of AD mice fed with a high-fat diet (TauTg-HFD mice) and quantitatively assessed its seeding activity using tau-biosensor cells. The phosphorylation levels of each phospho-site on tau were quantified by phosphoproteomic analyses using brain extracts derived from TauTg-HFD mice. There was a significant variation in the number of intracellular tau aggregates induced by TauTg-HFD mice-derived brain tau, which was not associated with the amount of total tau. We found that phosphorylation levels at seven phospho-sites were positively correlated with the number of intracellular tau aggregates (p < 0.05).

Conclusions: The increase in tau aggregation induced by DM might depend on the degree of phosphorylation at specific sites. Seven phospho-sites associated with tau seed activity induced by DM may contribute to the increased risk of AD.