Metformin Ameliorates A<i>β</i> 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<i>β</i>) 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<i>β</i>-induced pathology. Morris water maze and Y-maze results indicated that metformin could improve the learning and memory ability in APP^swe/PS1^dE9 (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 (<i>Syp</i>, <i>Ngf</i>, and <i>Bdnf</i>) in the brain. Metformin decreased oxidative stress (malondialdehyde and superoxide dismutase) and neuroinflammation (IL-1<i>β</i> and IL-6) in APP/PS1 mice. In addition, metformin obviously reduced the A<i>β</i> level in the brain of APP/PS1 mice. Metformin did not affect the enzyme activities and mRNA expression levels of A<i>β</i>-related secretases (<i>ADAM10</i>, <i>BACE1</i>, and <i>PS1</i>). Meanwhile, metformin also did not affect the mRNA expression levels of A<i>β</i>-related transporters (<i>LRP1</i> and <i>RAGE</i>). 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.