High-Fat Diet-Induced Diabetic Conditions Exacerbate Cognitive Impairment in a Mouse Model of Alzheimer's Disease Via a Specific Tau Phosphorylation Pattern.

Abstract

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.

• Authors: Y Ito, S Takeda, T Nakajima, A Oyama, H Takeshita, K Miki, Y Takami, Y Takeya, M Shimamura, H Rakugi, R Morishita
• Journal: The journal of prevention of Alzheimer's disease (J Prev Alzheimers Dis) Vol. 11 Issue 1 Pg. 138-148 ( 2024) ISSN: 2426-0266 [Electronic] Switzerland
• PMID: 38230726 (Publication Type: Journal Article)

Chemical References

• tau Proteins

Topics

• Mice
• Humans
• Animals
• Alzheimer Disease (metabolism)
• tau Proteins (metabolism)
• Phosphorylation
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Mice, Transgenic
• Diabetes Mellitus, Type 2
• Cognitive Dysfunction (complications)