SRF和心肌素调节脑血管细胞中LRP介导的β淀粉样蛋白清除。
SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells.
作者信息
Bell Robert D, Deane Rashid, Chow Nienwen, Long Xiaochun, Sagare Abhay, Singh Itender, Streb Jeffrey W, Guo Huang, Rubio Anna, Van Nostrand William, Miano Joseph M, Zlokovic Berislav V
机构信息
Center for Neurodegenerative and Vascular Brain Disorders, Arthur Kornberg Medical Research Building, University of Rochester School of Medicine & Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA.
出版信息
Nat Cell Biol. 2009 Feb;11(2):143-53. doi: 10.1038/ncb1819. Epub 2008 Dec 21.
Abstract
Amyloid beta-peptide (Abeta) deposition in cerebral vessels contributes to cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD). Here, we report that in AD patients and two mouse models of AD, overexpression of serum response factor (SRF) and myocardin (MYOCD) in cerebral vascular smooth muscle cells (VSMCs) generates an Abeta non-clearing VSMC phenotype through transactivation of sterol regulatory element binding protein-2, which downregulates low density lipoprotein receptor-related protein-1, a key Abeta clearance receptor. Hypoxia stimulated SRF/MYOCD expression in human cerebral VSMCs and in animal models of AD. We suggest that SRF and MYOCD function as a transcriptional switch, controlling Abeta cerebrovascular clearance and progression of AD.
摘要
淀粉样β肽（Aβ）在脑血管中的沉积会导致阿尔茨海默病（AD）中的脑淀粉样血管病（CAA）。在此，我们报告，在AD患者和两种AD小鼠模型中，脑血管平滑肌细胞（VSMC）中血清反应因子（SRF）和心肌素（MYOCD）的过表达通过固醇调节元件结合蛋白-2的反式激活产生一种Aβ清除障碍的VSMC表型，这会下调低密度脂蛋白受体相关蛋白-1，一种关键的Aβ清除受体。缺氧刺激人脑血管VSMC和AD动物模型中SRF/MYOCD的表达。我们认为SRF和MYOCD作为转录开关，控制Aβ的脑血管清除及AD的进展。
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Arch Neurol. 2008 Jun;65(6):790-5. doi: 10.1001/archneur.65.6.790.
2
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Neurobiol Dis. 2008 Apr;30(1):94-102. doi: 10.1016/j.nbd.2007.12.005. Epub 2008 Jan 5.
3
The blood-brain barrier in health and chronic neurodegenerative disorders.健康与慢性神经退行性疾病中的血脑屏障
Neuron. 2008 Jan 24;57(2):178-201. doi: 10.1016/j.neuron.2008.01.003.
4
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5
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6
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8
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