Reconsidering Repurposing: Long-term metformin treatment impairs cognition in Alzheimer’s model mice

Abstract

Abstract Metformin, a first-line anti-diabetic medication, may provide benefits against the pathogenesis of Alzheimer’s disease (AD) or “type 3 diabetes”. However, studies have demonstrated that metformin treatment may increase the risk of AD and aggravate its pathology. At present, no comprehensive investigation of the cognitive impact of chronic metformin treatment has been conducted. To address this issue, we chronically treated transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice with metformin (300 mg/kg/day) over 1 and 2 years, respectively. During this period, we assessed behaviours in a number of domains including motivation, attention, memory, visual discrimination, and cognitive flexibility using touchscreen operant chambers. We found that metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). In contrast, the chronic treatment caused impairments in memory retention and discrimination learning at an older age. In AD mice, metformin treatment also caused an impairment in learning and memory as assessed by the object-location paired-associates learning task. Consistent with these results, increased levels of β-amyloid oligomers, plaques, phosphorylated tau, and GSK3β expression were observed in the hippocampus of metformin-treated AD mice. Interestingly, chronic metformin treatment induced an increase in AMPKα1-subunit expression, which has been previously reported in the human AD brain. Potential confounding factors were ruled out since the levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12 were not altered by metformin. Our study indicates that the repurposing of metformin should be carefully reconsidered when this drug is used for persons with AD.