Metformin Ameliorates A? Pathology by Insulin-Degrading Enzyme in a Transgenic Mouse Model of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease. The accumulation of amyloid beta (A?) 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 A?-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-1? and IL-6) in APP/PS1 mice. In addition, metformin obviously reduced the A? level in the brain of APP/PS1 mice. Metformin did not affect the enzyme activities and mRNA expression levels of A?-related secretases (ADAM10, BACE1, and PS1). Meanwhile, metformin also did not affect the mRNA expression levels of A?-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.

SUBMITTER: Lu XY 

PROVIDER: S-EPMC7191377 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature