Metformin attenuates vascular pathology by increasing expression of insulin-degrading enzyme in a mixed model of cerebral amyloid angiopathy and type 2 diabetes mellitus.

ABSTRACT

Sporadic cerebral amyloid angiopathy (CAA), which is characterized by cerebrovascular amyloid ß (Aß) deposits, causes cerebral hemorrhages and dementia in elderly people. Metformin has been used to treat patients with type 2 diabetes mellitus (T2DM), and animal and clinical studies have reported therapeutic effects of metformin in Alzheimer's disease (AD). However, the therapeutic effects of metformin in CAA are unclear. Here, we used a mixed mouse model of CAA and T2DM (APP23-ob/ob) to investigate whether metformin has therapeutic effects on cerebrovascular Aß deposits. We dissolved metformin hydrochloride in water and administered it orally at 350 mg/kg/day. Treatments started when mice were 6 weeks old and continued until they were 15 months old. After we treated APP23-ob/ob mice with metformin, we counted the numbers of vessels with Aß and measured levels of Aß40 and Aß42 (soluble and insoluble), amyloid precursor protein (APP), APP-processing enzymes (α-, ß-, and γ-secretases), and Aß-degrading enzymes (insulin-degrading enzyme [IDE], neprilysin). Metformin significantly reduced cerebrovascular Aß deposits in APP23-ob/ob mice (p < .05). Compared with controls, metformin-treated APP23-ob/ob mice had significantly reduced Aß levels in the cerebral cortex (p < .05) and hippocampus (p < .05) and increased levels of IDE in the hippocampus (p < .01). Our results indicate that metformin attenuates the severity of CAA by enhancing Aß-cleaving IDE expression. The clinical application of metformin may lead to a novel therapeutic strategy in CAA treatment, especially in patients with T2DM.