Accelerated accumulation of amyloid β proteins on oxidatively damaged lipid membranes
Accelerated accumulation of amyloid β proteins on oxidatively damaged lipid membranes
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DOI：
10.1021/bi000619d
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发表时间：
2000-08-15
期刊：
影响因子：
2.9
通讯作者：
Axelsen, PH
中科院分区：
文献类型：
--
作者：
Koppaka, V;Axelsen, PH
阿尔茨海默氏病的完全发展的病变是由纤维状淀粉样β-蛋白组成的致密斑块，具有特征性且有序的β-折叠二级结构。由于初期病变最有可能在这些蛋白质首次被诱导形成 β-折叠二级结构时发生，因此了解诱导淀粉样β-蛋白采用这种构象的因素非常重要。在这项研究中，我们使用了一种新型红外光谱法，它可以表征蛋白质在各种脂质膜上的构象、方向和积累速率，以确定氧化损伤的磷脂膜是否会诱导 42 个残基淀粉样β-蛋白中β-折叠二级结构的形成。我们发现含有氧化损伤磷脂的膜比仅含有未氧化或饱和磷脂的膜积累淀粉样β蛋白的速度明显更快。当 3 mol% G(M1) 神经节苷脂掺入饱和磷脂酰胆碱膜时，也观察到加速积累。积累的蛋白质在氧化膜上更完全地采用β-折叠构象，并且β-折叠平面平行于膜平面取向。这些结果表明，氧化损伤的磷脂膜促进淀粉样β-蛋白形成β-片层，并且表明脂质过氧化在阿尔茨海默氏病的发病机制中可能发挥作用。
The fully developed lesion of Alzheimer's Disease is a dense plaque composed of fibrillar amyloid beta-proteins with a characteristic and well-ordered beta-sheet secondary structure. Because the incipient lesion most likely develops when these proteins are first induced to form beta-sheet secondary structure, it is important to understand factors that induce amyloid beta-proteins to adopt this conformation. In this investigation we used a novel form of infrared spectroscopy that can characterize the conformation, orientation, and rate of accumulation of the protein on various lipid membranes to determine whether oxidatively damaged phospholipid membranes induce the formation of beta-sheet secondary structure in a 42-residue amyloid beta-protein. We found that membranes containing oxidatively damaged phospholipids accumulated amyloid beta-protein significantly faster than membranes containing only unoxidized or saturated phospholipids. Accelerated accumulation was also seen when 3 mol % G(M1) ganglioside was incorporated into a saturated phosphatidylcholine membrane. The accumulated protein more completely adopted a beta-sheet conformation on oxidized membranes, and the plane of the beta-sheet was oriented parallel to the plane of the membrane. These results indicate that oxidatively damaged phospholipid membranes promote beta-sheet formation by amyloid beta-proteins, and they suggest a possible role for lipid peroxidation in the pathogenesis of Alzheimer's Disease.