Model membrane size-dependent amyloidogenesis of Alzheimer's amyloid-β peptides
Model membrane size-dependent amyloidogenesis of Alzheimer's amyloid-β peptides
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DOI：
10.1039/c6cp07774a
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发表时间：
2017-06-28
影响因子：
3.3
通讯作者：
Lee, Young-Ho
中科院分区：
文献类型：
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作者：
Kinoshita, Misaki;Kakimoto, Erina;Lee, Young-Ho
我们在此报告了淀粉样蛋白-β（A β）肽在小（SUV）和大单层囊泡（LUV）上形成淀粉样蛋白的机制，这些囊泡由1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱（POPC）脂质组成。尽管A β（1-42）在所用的所有POPC浓度下在SUV上形成原纤维，但滞后时间、伸长速率、最大硫磺素T强度和原纤维形态是不同的，表明多晶型淀粉样蛋白形成。LUV，在低POPC浓度，并没有显着影响原纤化动力学，但是，POPC浓度的增加抑制淀粉样蛋白的形成。虽然在SUV上形成的原纤维在稀释时显示出一些差异，但在有和没有囊泡的情况下形成的A β（1-42）原纤维的热稳定性没有观察到显著差异。SUV通过浓缩A β（1 - 40）显著促进A β（1 - 40）纤维化，而LUV对淀粉样蛋白生成没有影响。盐大大增加了囊泡上的A β（1-40）淀粉样蛋白生成。我们提出了囊泡大小依赖性A β淀粉样蛋白生成的综合模型。SUV中的不均匀包装缺陷可能会诱导淀粉样蛋白多态性的明显成核，并且随着LUV含量的增加，局部Ab浓度的降低会抑制淀粉样蛋白的形成。我们还指出，A β的C-末端疏水性对于膜上的淀粉样蛋白生成是重要的。
We herein report the mechanism of amyloid formation of amyloid-beta (A beta) peptides on small (SUV) and large unilamellar vesicles (LUVs), which consist of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids. Although A beta(1-42) formed fibrils on SUVs at all POPC concentrations used, the lag time, elongation rate, maximum thioflavin T intensity, and fibrillar morphology were distinct, indicating polymorphic amyloid formation. LUVs, at low POPC concentrations, did not markedly affect fibrillation kinetics; however, increases in POPC concentrations suppressed amyloid formation. No significant differences in the thermal stabilities of A beta(1-42) fibrils formed with and without vesicles were observed, although fibrils formed on SUVs showed some differences with dilution. SUVs markedly promoted A beta(1-40) fibrillation by condensing A beta(1-40), whereas no effects of LUVs on amyloidogenesis were detected. Salts greatly increased A beta(1-40) amyloidogenicity on vesicles. We proposed comprehensive models for vesicle size-dependent A beta amyloidogenesis. Inhomogeneous packing defects in SUVs may induce distinct nucleation in the polymorphisms of amyloids and decreasing local concentrations of Ab with higher amounts of LUVs inhibits amyloid formation. We also pointed out that C-terminal hydrophobicity of A beta is important for amyloidogenesis on membranes.