Amyloid β perturbs elevated heme flux induced with neuronal development.
Amyloid β perturbs elevated heme flux induced with neuronal development.
复制标题
淀粉样蛋白 β 扰乱神经元发育引起的血红素通量升高。
DOI：
10.1016/j.trci.2018.12.003
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Zhang,Li
中科院分区：
文献类型：
--
作者：
Vidal,Chantal;Daescu,Kelly;Fitzgerald,KeelyE;Starokadomska,Anna;Bezprozvanny,Ilya;Zhang,Li
血红素是神经元细胞线粒体呼吸和ATP生成的中心分子。因此，我们评估血红素代谢改变在阿尔茨海默病（AD）发病机制中的重要性。方法为了研究血红素代谢改变在阿尔茨海默病中的作用，我们鉴定了在阿尔茨海默病患者和淀粉样蛋白病理小鼠模型中表达改变的血红素相关蛋白。我们检测了在神经元分化过程中参与血红素合成、摄取、降解和功能的蛋白质水平，并表征了Aβ的作用。结果AD患者和小鼠中限制性血红素合成酶ALAS1和血红素降解酶HO-2的表达水平选择性降低。Aβ选择性地降低HO-2和血红素降解水平，在完全分化的神经细胞中，HO-2和血红素降解水平升高以支持神经元功能。我们的数据显示，血红素代谢的降低，特别是血红素降解和HO-2水平的降低，可能是AD发病的早期事件。
IntroductionHeme is a central molecule in mitochondrial respiration and ATP generation in neuronal cells. Thus, we assessed the importance of altered heme metabolism in Alzheimer's disease (AD) pathogenesis.MethodsTo investigate the role of altered heme metabolism in AD, we identified heme-related proteins whose expression is altered in AD patients and mouse models exhibiting amyloid pathology. We detected the levels of proteins involved in heme synthesis, uptake, degradation, and function during neuronal differentiation and characterized the effects of Aβ.ResultsWe found that the expression levels of the rate-limiting heme synthetic enzyme ALAS1 and heme degradation enzyme HO-2 are selectively decreased in AD patients and mice. Aβ selectively reduces the levels of HO-2 and heme degradation, which are elevated to support neuronal functions in fully differentiated neuronal cells.DiscussionOur data show that lowered heme metabolism, particularly the decreased levels of heme degradation and HO-2, is likely a very early event in AD pathogenesis.