Two types of Alzheimer's β-amyloid (1-40) peptide membrane interactions:: Aggregation preventing transmembrane anchoring Versus accelerated surface fibril formation
Two types of Alzheimer's β-amyloid (1-40) peptide membrane interactions:: Aggregation preventing transmembrane anchoring Versus accelerated surface fibril formation
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DOI：
10.1016/j.jmb.2003.11.046
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发表时间：
2004-01-23
影响因子：
5.6
通讯作者：
Gröbner, G
中科院分区：
文献类型：
--
作者：
Bokvist, M;Lindström, F;Gröbner, G
长39-42个氨基酸，两亲性淀粉样蛋白- p肽（Abeta）是参与阿尔茨海默病（AD）的关键成分之一。在AD的神经病理学中，Abeta可能通过与神经元膜的相互作用发挥其神经毒性作用。在我们的研究中，P-31 MAS NMR（魔角自旋核磁共振）和CD（圆二色）光谱的结合表明，在两种不同的情况下，超分子Abeta（1-40）膜组件的功能组织存在根本差异，这可能对AD有潜在的影响：Abeta肽可以通过蛋白水解裂解牢固地锚定在膜上，从而阻止释放和聚集，也可以通过加速聚集与膜表面结合产生根本性的不良影响，导致神经元凋亡细胞死亡。酸性脂质通过在碱性Lys28残基和带负电荷的膜界面之间的静电锚定将Abeta（1-40）的疏水跨膜c端部分（残基29-40）稳定在α -螺旋构象中，从而阻止插入膜的Abeta（1-40）的释放。然而，如果Abeta（1-40）作为可溶性单体释放，带电荷的膜充当二维聚集模板，其中带电脂质（可能的病理降解产物）数量的增加导致表面相关Abeta（1-40）肽的急剧积累，随后加速聚集成有毒结构。这些结果表明，肽-膜组装的两种不同分子机制参与了Abeta的病理生理，Abeta-脂质相互作用的精细平衡类型阻止了Abeta从神经元膜的释放，被Abeta-膜组装过度补偿，导致阿尔茨海默病中有毒的β结构聚集体。因此，Abeta肽与神经元膜的病理相互作用可能不仅取决于肽的寡聚化状态，还取决于继承自Abeta起源的超分子Abeta-膜组装的类型和性质。(C) 2003 Elsevier Ltd.版权所有。
The 39-42 amino acid long, amphipathic amyloid-P peptide (Abeta) is one of the key components involved in Alzheimer's disease (AD). In the neuropathology of AD, Abeta presumably exerts its neurotoxic action via interactions with neuronal membranes. In our studies a combination of P-31 MAS NMR (magic angle spinning nuclear magnetic resonance) and CD (circular dichroism) spectroscopy suggest fundamental differences in the functional organization of supramolecular Abeta(1-40) membrane assemblies for two different scenarios with potential implication in AD: Abeta peptide can either be firmly anchored in a membrane upon proteolytic cleavage, thereby being prevented against release and aggregation, or it can have fundamentally adverse effects when bound to membrane surfaces by undergoing accelerated aggregation, causing neuronal apoptotic cell death. Acidic lipids can prevent release of membrane inserted Abeta(1-40) by stabilizing its hydrophobic transmembrane C-terminal part (residue 29-40) in an alpha-helical conformation via an electrostatic anchor between its basic Lys28 residue and the negatively charged membrane interface. However, if Abeta(1-40) is released as a soluble monomer, charged membranes act as two-dimensional aggregation-templates where an increasing amount of charged lipids (possible pathological degradation products) causes a dramatic accumulation of surface-associated Abeta(1-40) peptide followed by accelerated aggregation into toxic structures. These results suggest that two different molecular mechanisms of peptide-membrane assemblies are involved in Abeta's pathophysiology with the finely balanced type of Abeta-lipid interactions against release of Abeta from neuronal membranes being overcompensated by an Abeta-membrane assembly which causes toxic beta-structured aggregates in AD. Therefore, pathological interactions of Abeta peptide with neuronal membranes might not only depend on the oligomerization state of the peptide, but also the type and nature of the supramolecular Abeta-membrane assemblies inherited from Abeta's origin. (C) 2003 Elsevier Ltd. All rights reserved.