Cribbs D H, Pike C J, Weinstein S L, Velazquez P, Cotman C W
Institute for Brain Aging and Dementia, Departments of Psychobiology, University of California Irvine, Irvine, California 92697-4540, USA.
J Biol Chem. 1997 Mar 14;272(11):7431-6. doi: 10.1074/jbc.272.11.7431.
The amyloidogenic peptide beta-amyloid has previously been shown to bind to neurons in the form of fibrillar clusters on the cell surface, which induces neurodegeneration and activates a program of cell death characteristic of apoptosis. To further investigate the mechanism of Abeta neurotoxicity, we synthesized the all-D- and all-L-stereoisomers of the neurotoxic truncated form of Abeta (Abeta25-35) and the full-length peptide (Abeta1-42) and compared their physical and biological properties. We report that the purified peptides exhibit nearly identical structural and assembly characteristics as assessed by high performance liquid chromatography, electron microscopy, circular dichroism, and sedimentation analysis. In addition, both enantiomers induce similar levels of toxicity in cultured hippocampal neurons. These data suggest that the neurotoxic actions of Abeta result not from stereoisomer-specific ligand-receptor interactions but rather from Abeta cellular interactions in which fibril features of the amyloidogenic peptide are a critical feature. The promiscuous nature of these beta-sheet-containing fibrils suggests that the accumulation of amyloidogenic peptides in vivo as extracellular deposits represents a site of bioactive peptides with the ability to provide inappropriate signals to cells leading to cellular degeneration and disease.
淀粉样蛋白生成肽β-淀粉样蛋白先前已被证明以细胞表面纤维状聚集体的形式与神经元结合，这会诱导神经退行性变并激活凋亡特征性的细胞死亡程序。为了进一步研究β-淀粉样蛋白神经毒性的机制，我们合成了神经毒性截短形式的β-淀粉样蛋白（β-淀粉样蛋白25-35）和全长肽（β-淀粉样蛋白1-42）的全D型和全L型立体异构体，并比较了它们的物理和生物学特性。我们报告说，通过高效液相色谱、电子显微镜、圆二色性和沉降分析评估，纯化后的肽表现出几乎相同的结构和组装特征。此外，两种对映体在培养的海马神经元中诱导相似水平的毒性。这些数据表明，β-淀粉样蛋白的神经毒性作用并非源于立体异构体特异性配体-受体相互作用，而是源于β-淀粉样蛋白与细胞的相互作用，其中淀粉样蛋白生成肽的纤维特征是一个关键特征。这些含β折叠的纤维的混杂性质表明，淀粉样蛋白生成肽在体内作为细胞外沉积物的积累代表了一个生物活性肽的位点，这些肽能够向细胞提供不适当的信号，导致细胞变性和疾病。
