Aβ efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas.
Aβ efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas.
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DOI：
10.1038/s42003-022-04398-2
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发表时间：
2023-01-03
影响因子：
5.9
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中科院分区：
文献类型：
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脑β-淀粉样蛋白（Aβ）消除的血管通路损伤有助于阿尔茨海默病（AD）。血管损伤通常与糖尿病有关。我们在人体组织和ad模型大鼠中发现，胰腺分泌的血源性胰岛淀粉样多肽（amylin）干扰了大脑中Aβ的清除。阿尔茨海默病患者的血胰淀素浓度高于认知能力未受影响的人。淀粉样蛋白形成的胰淀素在循环单核细胞中积累，并与脑微血管内的Aβ共同沉积，可能与炎症有关。在大鼠中，胰腺表达淀粉样蛋白的人胰淀素确实诱导脑血管炎症和胰淀素- β共沉积。lrp1介导的Aβ通过血脑屏障的转运和沿血管壁的间质液引流对Aβ的清除受到损害，这表明Aβ在血管周围空间的沉积。在分子水平上，脑血管淀粉酶沉积改变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趋同数据表明，改变血源性胰淀素可能会减少脑血管胰淀素沉积和Aβ病理。来自人类和实验动物的越来越多的数据表明，改变血源性胰淀素可能会减少阿尔茨海默氏症患者大脑中的脑血管胰淀素沉积和Aβ病理。
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. Converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology in Alzheimer’s disease brains.
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DOI：
10.1038/nrneurol.2017.185
发表时间：
2018-03
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Arnold SE;Arvanitakis Z;Macauley-Rambach SL;Koenig AM;Wang HY;Ahima RS;Craft S;Gandy S;Buettner C;Stoeckel LE;Holtzman DM;Nathan DM
通讯作者：
Nathan DM
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
--
作者：
Luchsinger, Jose A.;Reitz, Christiane;Mayeux, Richard
通讯作者：
Mayeux, Richard
影响因子：
48
作者：
Kellar, Derek;Craft, Suzanne
通讯作者：
Craft, Suzanne
影响因子：
8.8
作者：
Leslie PL;Franklin DA;Liu Y;Zhang Y
通讯作者：
Zhang Y