Metformin Ameliorates Aβ Pathology by Insulin-Degrading Enzyme in a Transgenic Mouse Model of Alzheimer’s Disease

Abstract EN

Alzheimer’s disease (AD) is the most common neurodegenerative disease.

The accumulation of amyloid beta (Aβ) is the main pathology of AD.

Metformin, a well-known antidiabetic drug, has been reported to have AD-protective effect.

However, the mechanism is still unclear.

In this study, we tried to figure out whether metformin could activate insulin-degrading enzyme (IDE) to ameliorate Aβ-induced pathology.

Morris water maze and Y-maze results indicated that metformin could improve the learning and memory ability in APPswe/PS1dE9 (APP/PS1) transgenic mice.

18F-FDG PET-CT result showed that metformin could ameliorate the neural dysfunction in APP/PS1 transgenic mice.

PCR analysis showed that metformin could effectively improve the mRNA expression level of nerve and synapse-related genes (Syp, Ngf, and Bdnf) in the brain.

Metformin decreased oxidative stress (malondialdehyde and superoxide dismutase) and neuroinflammation (IL-1β and IL-6) in APP/PS1 mice.

In addition, metformin obviously reduced the Aβ level in the brain of APP/PS1 mice.

Metformin did not affect the enzyme activities and mRNA expression levels of Aβ-related secretases (ADAM10, BACE1, and PS1).

Meanwhile, metformin also did not affect the mRNA expression levels of Aβ-related transporters (LRP1 and RAGE).

Metformin increased the protein levels of p-AMPK and IDE in the brain of APP/PS1 mice, which might be the key mechanism of metformin on AD.

In conclusion, the well-known antidiabetic drug, metformin, could be a promising drug for AD treatment.