Metformin Ameliorates Aβ 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 (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.

Hyperbaric oxygen therapy alleviates vascular dysfunction and amyloid burden in an Alzheimer’s disease mouse model and in elderly patients

“…In addition, HBOT elevated IDE and LRP1 levels, thus promoting Aβ degradation and clearance. These findings are in accordance with evidence showing that elevating either activity of the degradation pathway by enhancing IDE levels [ 76 , 77 ] or of clearance pathway by changing LRP1 levels [ 78 ] leads to a reduction in amyloid burden. Our finding that the number of microglia per plaque volume increased following HBOT suggests that microglia were recruited to plaques, possibly supporting plaque degradation [ 79 , 80 ].…”

Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice

“…It is prescribed to the elderly population and has relatively safe profile even after chronic treatment [ 93 ]. Application of metformin has been shown beneficial in restoring energy homeostasis in the brain of APP/PS1 mice providing additional support for our findings [ 94 ]. A recent study conducted in a large Finish population of older people with diabetes demonstrated that long-term and high-dose metformin use do not increase incidences of AD and is associated with a lower risk of developing AD [ 95 ].…”

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

“…Metformin also restored spine density, surface AMPA subunit GluA1 trafficking, LTP expression and spatial memory in the APP/PS1 mouse by inhibiting cyclin-dependent kinase 5 hyper-activation and cyclin-dependent kinase 5-dependent tau hyperactivation( Wang et al, 2020 ). Furthermore, metformin could activate AMPK and insulin-degrading enzyme in the brain of APP/PS 1 mice, which might be the key neuroprotection mechanism of metformin( Lu et al, 2020 ). Metformin treatment for 8 weeks improved memory in the SAMP8 mouse model of sporadic AD, which was associated with the decreased levels of APPc99 and pTau404( Farr et al, 2019 ).…”