Metformin attenuates vascular pathology by increasing expression of insulin-degrading enzyme in a mixed model of cerebral amyloid angiopathy and type 2 diabetes mellitus
Metformin attenuates vascular pathology by increasing expression of insulin-degrading enzyme in a mixed model of cerebral amyloid angiopathy and type 2 diabetes mellitus
复制标题
DOI：
10.1016/j.neulet.2021.136136
复制
发表时间：
2021-08-07
影响因子：
2.5
通讯作者：
Ueda, Mitsuharu
中科院分区：
文献类型：
--
作者：
Inoue, Yasuteru;Masuda, Teruaki;Ueda, Mitsuharu
散发性脑淀粉样血管病（CAA）以脑血管β淀粉样蛋白（Aβ）沉积为特征，可导致老年人脑出血和痴呆。二甲双胍已用于治疗 2 型糖尿病 (T2DM) 患者，动物和临床研究报告了二甲双胍对阿尔茨海默病 (AD) 的治疗效果。然而，二甲双胍对 CAA 的治疗效果尚不清楚。在这里，我们使用 CAA 和 T2DM 混合小鼠模型 (APP23-ob/ob) 来研究二甲双胍是否对脑血管 Aβ 沉积物具有治疗作用。我们将盐酸二甲双胍溶解在水中，并以 350 mg/kg/天的剂量口服。治疗从小鼠 6 周大时开始，一直持续到 15 个月大。在我们用二甲双胍治疗 APP23-ob/ob 小鼠后，我们计算了 Aβ 血管的数量，并测量了 Aβ40 和 Aβ42（可溶性和不溶性）、淀粉样前体蛋白 (APP)、APP 加工酶（α、β 和 γ 分泌酶）和 Aβ 降解酶（胰岛素降解酶）的水平。 酶[IDE]、脑啡肽酶）。二甲双胍显着减少 APP23-ob/ob 小鼠的脑血管 Aβ 沉积 (p < .05)。与对照组相比，二甲双胍治疗的 APP23-ob/ob 小鼠大脑皮层 (p < .05) 和海马 (p < .05) 中的 Aβ 水平显着降低，海马中 IDE 水平升高 (p < .01)。我们的结果表明，二甲双胍通过增强 A beta 裂解 IDE 的表达来减轻 CAA 的严重程度。二甲双胍的临床应用可能会为CAA治疗带来一种新的治疗策略，特别是对于T2DM患者。
Sporadic cerebral amyloid angiopathy (CAA), which is characterized by cerebrovascular amyloid beta (A beta) 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 A beta 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 A beta and measured levels of A beta 40 and A beta 42 (soluble and insoluble), amyloid precursor protein (APP), APP-processing enzymes (alpha-, beta-, and gamma-secretases), and A beta-degrading enzymes (insulin-degrading enzyme [IDE], neprilysin). Metformin significantly reduced cerebrovascular A beta deposits in APP23-ob/ob mice (p < .05). Compared with controls, metformin-treated APP23-ob/ob mice had significantly reduced A beta 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 A beta-cleaving IDE expression. The clinical application of metformin may lead to a novel therapeutic strategy in CAA treatment, especially in patients with T2DM.