Type II Diabetes Mellitus Accelerates Age-Dependent Aβ Pathology in Cynomolgus Monkey Brain

Area of Science:

• Neuroscience
• Endocrinology
• Pathology

Background:

• Diabetes mellitus (DM) is a significant risk factor for Alzheimer's disease (AD).
• The precise mechanisms linking DM to accelerated AD pathology remain unclear.
• Cynomolgus monkeys develop spontaneous AD pathology and can develop type II DM (T2DM), making them a relevant model.

Purpose of the Study:

• To investigate the relationship between T2DM and AD pathology in cynomolgus monkeys.
• To explore how T2DM influences the development of senile plaques (SPs) and neurofibrillary tangles (NFTs).
• To examine the role of endocytic pathology in T2DM-associated acceleration of AD.

Main Methods:

• Comparative analysis of brain tissue from T2DM-affected and healthy control cynomolgus monkeys.
• Histopathological examination for senile plaques (SPs) and neurofibrillary tangles (NFTs).
• Assessment of age-related endocytic pathology, including intraneuronal endosome accumulation.

Main Results:

• SPs were observed approximately 5 years earlier in the frontal and temporal cortices of T2DM-affected monkeys compared to controls.
• Age-related endocytic pathology, characterized by enlarged intraneuronal endosomes, was more severe in T2DM-affected brains.
• These findings suggest T2DM exacerbates age-related endocytic dysfunction.

Conclusions:

• T2DM accelerates the onset and progression of AD pathology, specifically SP formation, in cynomolgus monkeys.
• The acceleration of AD pathology by T2DM may be mediated by the exacerbation of age-related endocytic dysfunction.
• This study highlights the utility of cynomolgus monkeys for modeling T2DM-AD interactions and suggests endocytic pathways as therapeutic targets.