Dante Silvia, Hauss Thomas, Dencher Norbert A
Physical Biochemistry, Darmstadt University of Technology, Petersenstrasse 22, D-64287 Darmstadt, Germany.
Biophys J. 2002 Nov;83(5):2610-6. doi: 10.1016/S0006-3495(02)75271-5.
Neuronal plasma membranes are thought to be the primary target of the neurotoxic beta-amyloid peptides (Abeta) in the pathogenesis of the Alzheimer's disease. Histologically, Abeta peptides are observed as extracellular macroscopic senile plaques, and most biophysical techniques have indicated the presence of Abeta close to the lipid headgroup region but not in the core of the membrane bilayers. The focus of this study is an investigation of the interaction between Abeta and lipid bilayers from a structural point of view. Neutron diffraction with the use of selectively deuterated amino acids has allowed us to determine unambiguously the position of the neurotoxic fragment Abeta (25-35) in the membrane. Two populations of the peptide are detected, one in the aqueous vicinity of the membrane surface and the second inside the hydrophobic core of the lipid membrane. The location of the C terminus was studied in two different lipid compositions and was found to be dependent on the surface charge of the membrane. The localization of beta-amyloid peptides in cell membranes will offer new insights on their mechanism in the neurodegenerative process associated with Alzheimer's disease and might provide clues for therapeutic developments.
神经元质膜被认为是阿尔茨海默病发病机制中神经毒性β-淀粉样肽（Aβ）的主要作用靶点。在组织学上，Aβ肽表现为细胞外肉眼可见的老年斑，并且大多数生物物理技术表明Aβ存在于靠近脂质头部基团区域，而非在膜双层的核心部位。本研究的重点是从结构角度研究Aβ与脂质双层之间的相互作用。利用选择性氘代氨基酸进行中子衍射，使我们能够明确确定神经毒性片段Aβ（25 - 35）在膜中的位置。检测到该肽存在两种分布状态，一种在膜表面的水相附近，另一种在脂质膜的疏水核心内部。在两种不同的脂质组成中研究了C末端的位置，发现其依赖于膜的表面电荷。β-淀粉样肽在细胞膜中的定位将为其在与阿尔茨海默病相关的神经退行性过程中的作用机制提供新的见解，并可能为治疗发展提供线索。
