Amyloid-β peptide binds with heme to form a peroxidase:: Relationship to the cytopathologies of Alzheimer's disease
Amyloid-β peptide binds with heme to form a peroxidase:: Relationship to the cytopathologies of Alzheimer's disease
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DOI：
10.1073/pnas.0600134103
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发表时间：
2006-02-28
影响因子：
11.1
通讯作者：
Boyle, K
中科院分区：
文献类型：
--
作者：
Atamna, H;Boyle, K
淀粉样β肽（A β）是阿尔茨海默病（AD）中的毒性物质，尽管引起神经变性的机制尚不清楚。我们先前提出了一种机制，其中过量的A β与调节性血红素结合，引发功能性血红素缺乏症（HD），导致AD的关键细胞病理学。我们证明了HD触发氧化剂的释放（例如，H2 O2）从线粒体由于损失的复合物IV，其中含有血红素-a。现在，我们增加了更多的证据，表明A β在体内与调节血红素结合是A β引起HD的机制。血红素与A β结合，从而通过在无细胞系统中形成A β-血红素复合物来防止A β聚集。我们认为，这种复杂的消耗调节血红素，这将解释增加血红素合成和铁的摄取，我们观察到在人类神经母细胞瘤细胞。A β-血红素复合物被证明是一种过氧化物酶，它催化H2 O2氧化5-羟色胺和3，4-二羟基苯丙氨酸。姜黄素可以降低AD小鼠模型大脑中的氧化损伤，抑制这种过氧化物酶。A β与血红素的结合支持了一种统一的机制，通过该机制，过量的A β诱导HD，引起大分子的氧化损伤，并消耗特定的神经递质。调节血红素与过量的A β的线粒体功能障碍和神经毒性和AD的其他细胞病理学的结合的相关性进行了讨论。
Amyloid-beta peptide (A beta) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive A beta binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H2O2) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that A beta binding to regulatory heme in vivo is the mechanism by which A beta causes HD. Heme binds to A beta, thus preventing A beta aggregation by forming an A beta-heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The A beta-heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H2O2. Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of A beta to heme supports a unifying mechanism by which excessive A beta induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive A beta for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.