Hensley K, Carney J M, Mattson M P, Aksenova M, Harris M, Wu J F, Floyd R A, Butterfield D A
Department of Chemistry, University of Kentucky, Lexington 40506.
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3270-4. doi: 10.1073/pnas.91.8.3270.
beta-Amyloid is a 39- to 43-amino-acid neurotoxic peptide that aggregates to form the core of Alzheimer disease-associated senile (amyloid) plaques. No satisfactory hypothesis has yet been proposed to explain the mechanism of beta-amyloid aggregation and toxicity. We present mass spectrometric and electron paramagnetic resonance spin trapping evidence that beta-amyloid, in aqueous solution, fragments and generates free radical peptides. beta-Amyloid fragments, at concentrations that previously have been shown to be neurotoxic to cultured neurons, can inactivate oxidation-sensitive glutamine synthetase and creatine kinase enzymes. Also, salicylate hydroxylation assays indicate that reactive oxygen species are generated by the beta-amyloid-(25-35) fragment during cell-free incubation. These results are formulated into a free radical-based unifying hypothesis for neurotoxicity of beta-amyloid and are discussed with reference to membrane molecular alterations in Alzheimer disease.
β-淀粉样蛋白是一种由39至43个氨基酸组成的神经毒性肽，它会聚集形成与阿尔茨海默病相关的老年（淀粉样）斑块的核心。目前尚未提出令人满意的假说来解释β-淀粉样蛋白聚集和毒性的机制。我们提供了质谱和电子顺磁共振自旋捕获证据，证明β-淀粉样蛋白在水溶液中会断裂并产生自由基肽。β-淀粉样蛋白片段在先前已被证明对培养神经元具有神经毒性的浓度下，能够使氧化敏感的谷氨酰胺合成酶和肌酸激酶失活。此外，水杨酸羟化测定表明，在无细胞孵育过程中，β-淀粉样蛋白（25-35）片段会产生活性氧。这些结果被整合为一个基于自由基的β-淀粉样蛋白神经毒性统一假说，并结合阿尔茨海默病中的膜分子改变进行了讨论。
