HIGH-FAT DIET-INDUCED DIABETIC CONDITIONS EXACERBATE COGNITIVE IMPAIRMENT IN A MOUSE MODEL OF ALZHEIMER’S DISEASE VIA A SPECIFIC TAU PHOSPHORYLATION PATTERN
Y. Ito, S. Takeda, T. Nakajima, A. Oyama, H. Takeshita, K. Miki, Y. Takami, Y. Takeya, M. Shimamura, H. Rakugi, R. Morishita
BACKGROUND: Epidemiological evidence has demonstrated a clear association between diabetes mellitus and increased risk of Alzheimer’s disease (AD). Cerebral accumulation of phosphorylated tau aggregates, a cardinal neuropathological feature of AD, is associated with neurodegeneration and cognitive decline. Clinical and experimental studies indicate that diabetes mellitus affects the development of tau pathology; however, the underlying molecular mechanisms remain unknown.
OBJECTIVE: In the present study, we used a unique diabetic AD mouse model to investigate the changes in tau phosphorylation patterns occurring in the diabetic brain.
DESIGN: Tau-transgenic mice were fed a high-fat diet (n = 24) to model diabetes mellitus. These mice developed prominent obesity, severe insulin resistance, and mild hyperglycemia, which led to early-onset neurodegeneration and behavioral impairment associated with the accumulation of hyperphosphorylated tau aggregates.
RESULTS: Comprehensive phosphoproteomic analysis revealed a unique tau phosphorylation signature in the brains of mice with diabetic AD. Bioinformatic analysis of the phosphoproteomics data revealed putative tau-related kinases and cell signaling pathways involved in the interaction between diabetes mellitus and AD.
CONCLUSION: These findings offer potential novel targets that can be used to develop tau-based therapies and biomarkers for use in AD.
Y. Ito ; S. Takeda ; T. Nakajima ; A. Oyama ; H. Takeshita ; K. Miki ; Y. Takami ; Y. Takeya ; M. Shimamura ; H. Rakugi ; R. Morishita ; (2023): High-Fat Diet-Induced Diabetic Conditions Exacerbate Cognitive Impairment in a Mouse Model of Alzheimer’s Disease Via a Specific Tau Phosphorylation Pattern. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.85