Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
The Research Center for Healthy Metabolism, University of Kentucky, Lexington, KY, USA.
Commun Biol. 2023 Jan 3;6(1):2. doi: 10.1038/s42003-022-04398-2.
Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology.
血管途径清除脑β-淀粉样蛋白（Aβ）的障碍导致阿尔茨海默病（AD）。血管损伤通常与糖尿病有关。在这里，我们在人体组织和 AD 模型大鼠中表明，从胰腺分泌的血液胰岛淀粉样多肽（胰岛淀粉样肽）扰乱了脑 Aβ的清除。AD 患者血液中的胰岛淀粉样肽浓度高于认知正常者。形成淀粉样的胰岛淀粉样肽在循环单核细胞中积累，并与脑微血管中的 Aβ共同沉积，可能涉及炎症。在大鼠中，胰腺表达的形成淀粉样的人胰岛淀粉样肽确实会引起脑血管炎症和胰岛淀粉样肽-Aβ共沉积。LRP1 介导的 Aβ通过血脑屏障的转运和通过沿血管壁的间质液引流清除 Aβ的能力受损，这表现为血管周围间隙的 Aβ沉积。在分子水平上，脑血管胰岛淀粉样肽沉积改变了与免疫和缺氧相关的脑基因表达。这些来自人类和实验动物的综合数据表明，改变血液中的胰岛淀粉样肽可能会减少脑血管胰岛淀粉样肽沉积和 Aβ病理。
