Heme binding to Amyloid-β peptide: Mechanistic role in Alzheimer's disease
Heme binding to Amyloid-β peptide: Mechanistic role in Alzheimer's disease
复制标题
DOI：
10.3233/jad-2006-102-310
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
H. Atamna
中科院分区：
文献类型：
--
作者：
H. Atamna
遗传学、生物化学和免疫学证据支持淀粉样蛋白-β（Abeta）肽在阿尔茨海默病（AD）的病理生理学中的机制作用。Abeta似乎触发AD的大多数不同的细胞病理学（例如铁稳态和线粒体复合物IV的丧失），这可能引发突触功能障碍、代谢减退和记忆丧失。然而，将Abeta与AD的神经变性联系起来的分子机制尚不清楚。我们已经提供了证据证明血红素在AD的重要细胞病理学中的关键作用，假设AD患者脑中血红素的功能缺陷。我们发现血红素与Abeta结合，形成复合物（Abeta-heme），这证明了支持这一假设所需的β和血红素之间的分子联系。血红素通过形成A β-血红素来阻止A β的聚集，表明A β-血红素可以阻止体内A β的聚集。然而，缺点是Abeta-heme是一种过氧化物酶，如果不受调节，可能会不加选择地氧化各种生物分子。此外，AD脑中Abeta的过量产生可能与调节血红素结合并限制其生物利用度，从而产生血红素缺乏症。调节血红素调节血红素合成，铁稳态，特定的信号通路，和中间代谢。介绍了一种新的Abeta诱导的血红素缺乏导致线粒体功能障碍、Abeta-血红素过氧化物酶和代谢活性改变的模型。遗传，营养和毒理学因素影响血红素代谢将讨论相关的AD。
Genetic, biochemical, and immunological evidences support a mechanistic role for amyloid-beta (Abeta) peptide in the pathophysiology of Alzheimer's disease (AD). Abeta appears to trigger most of the disparate cytopathologies of AD (e.g. loss of iron homeostasis and mitochondrial complex IV), which may initiate synaptic dysfunction, hypometabolism, and memory loss. However, the molecular mechanism that links Abeta to the neurodegeneration of AD is not clear. We have provided evidence for heme's key role in the important cytopathologies of AD, hypothesizing a functional deficiency for heme in the brains of AD patients. The molecular link between beta and heme required to support this hypothesis was demonstrated by our discovery that heme binds with Abeta, forming a complex (Abeta-heme). Heme prevented the aggregation of Abeta by forming Abeta-heme, suggesting Abeta-heme may prevent Abeta aggregation in vivo. The downside, however, is that Abeta-heme is a peroxidase, which if not regulated might indiscriminately oxidize diverse biomolecules. Additionally, excessive production of Abeta in AD brain may bind to and restrict the bioavailability of regulatory heme, creating a condition of heme-deficiency. Regulatory heme regulates heme synthesis, iron homeostasis, specific signaling pathways, and intermediary metabolism. A novel model of Abeta-induced heme-deficiency leading to mitochondrial dysfunction, Abeta-heme peroxidase, and altered metabolic activity is presented. Genetic, nutritional, and toxicological factors that influence heme metabolism will be discussed in relevance to AD.