Characterization of preclinical Alzheimer's disease model: spontaneous type 2 diabetic cynomolgus monkeys with systemic pro-inflammation, positive biomarkers and developing AD-like pathology

Xinxin Huang ^1,2, Shanshan Huang ^1,2, Fangyan Fu ^1,2

⁰State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Sanya, 572025, China.

Alzheimer's Research & Therapy +

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March 8, 2024

View abstract on PubMed

Summary

Type 2 diabetes mellitus (T2DM) in monkeys shows increased inflammation and Alzheimer's disease (AD) biomarkers, suggesting a preclinical AD model. This research offers a new model for studying early AD development and potential interventions.

Area Of Science

Neuroscience
Endocrinology
Pathology

Background

Predicting and diagnosing Alzheimer's disease (AD) at early stages is crucial for effective prevention and treatment.
A significant barrier to early AD detection is the lack of a suitable preclinical model.
Type 2 diabetes mellitus (T2DM) is increasingly recognized as a risk factor for AD.

Purpose Of The Study

To investigate the potential of T2DM in non-human primates as a preclinical model for Alzheimer's disease.
To evaluate the presence of pro-inflammatory cytokines and AD pathological biomarkers in T2DM monkeys.
To assess AD-like neuropathological changes in the brains of T2DM monkeys.

Main Methods

In vivo evaluation of 18 monkeys (9 T2DM, 9 controls) for pro-inflammatory cytokines and AD biomarkers using ELISA and Simoa technology.
Ex vivo assessment of AD-like pathology in 9 monkeys (6 T2DM, 3 controls) using immunohistochemistry, Bielschowsky's silver, Congo red, and Thioflavin S staining.
Evaluation of synaptic damage and neurodegeneration via immunofluorescence.

Main Results

T2DM monkeys exhibited elevated pro-inflammatory cytokines (e.g., TNF-α) in blood and brain.
Decreased levels of β-amyloid (Aβ) 42 and Aβ40 were observed in the peripheral blood of T2DM monkeys.
AD-like brain pathology in T2DM monkeys included Aβ plaque deposition, tau pathology (neurofibrillary tangles), activated microglia and astrocytes, and synaptic impairment, but no neuronal death.

Conclusions

T2DM monkeys display systemic inflammation, AD biomarkers, and developing AD-like neuropathology.
The observed changes suggest that T2DM monkeys represent a viable preclinical model for Alzheimer's disease.
This model can facilitate research into the early mechanisms of AD and the development of therapeutic strategies.

Keywords:

Alzheimer’s disease Biomarkers Cynomolgus monkeys Preclinical Pro-inflammatory factor Type 2 diabetes mellitus