Ly Han, Verma Nirmal, Wu Fengen, Liu Miao, Saatman Kathryn E, Nelson Peter T, Slevin John T, Goldstein Larry B, Biessels Geert Jan, Despa Florin
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY.
Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY.
Ann Neurol. 2017 Aug;82(2):208-222. doi: 10.1002/ana.24992. Epub 2017 Jul 29.
The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins.
Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells ex vivo.
Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type 2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury, and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats.
These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. Ann Neurol 2017;82:208-222.
2型糖尿病和痴呆患者的脑血管中有胰岛淀粉样多肽沉积，胰岛淀粉样多肽是一种与胰岛素共同分泌的淀粉样生成激素。目前尚不清楚血管胰岛淀粉样多肽沉积是血管损伤的结果还是触发因素。我们检验了以下假设：血管胰岛淀粉样多肽沉积会导致内皮功能障碍和微血管损伤，并受血浆载脂蛋白介导的胰岛淀粉样多肽在脑内转运的调节。
利用胰腺中过表达淀粉样生成（人）胰岛淀粉样多肽的大鼠（HIP大鼠）和静脉注射聚集态胰岛淀粉样多肽的胰岛淀粉样多肽基因敲除（AKO）大鼠进行体内表型分析。我们还对人脑组织进行了生化分析，并研究了聚集态胰岛淀粉样多肽对体外培养的内皮细胞的影响。
2型糖尿病和痴呆患者、HIP大鼠以及注射了聚集态胰岛淀粉样多肽的AKO大鼠的脑血管中，胰岛淀粉样多肽沉积与血管壁破坏及周围神经纤维异常有关。HIP大鼠存在脑微出血、白质损伤和神经功能缺损。血管胰岛淀粉样多肽沉积导致内皮细胞覆盖和紧密连接丧失。在AKO大鼠中静脉注射人胰岛淀粉样多肽，或联合注射人胰岛淀粉样多肽和载脂蛋白E4，结果显示胰岛淀粉样多肽与血浆载脂蛋白结合。静脉注射载脂蛋白E4加剧了HIP大鼠脑中聚集态胰岛淀粉样多肽的蓄积和血管病变。
这些数据表明血管胰岛淀粉样多肽沉积是脑内皮功能障碍的触发因素，受血浆载脂蛋白调节，是糖尿病相关痴呆和中风的潜在治疗靶点。《神经病学纪事》2017年；82:208 - 222。
