A MODEL FOR BETA-AMYLOID AGGREGATION AND NEUROTOXICITY BASED ON FREE-RADICAL GENERATION BY THE PEPTIDE - RELEVANCE TO ALZHEIMER-DISEASE
A MODEL FOR BETA-AMYLOID AGGREGATION AND NEUROTOXICITY BASED ON FREE-RADICAL GENERATION BY THE PEPTIDE - RELEVANCE TO ALZHEIMER-DISEASE
复制标题
DOI：
10.1073/pnas.91.8.3270
复制
发表时间：
1994-04-12
影响因子：
11.1
通讯作者：
BUTTERFIELD, DA
中科院分区：
文献类型：
--
作者：
HENSLEY, K;CARNEY, JM;BUTTERFIELD, DA
β-淀粉样蛋白是一种39- 43个氨基酸的神经毒性肽，其聚集形成阿尔茨海默病相关的老年（淀粉样蛋白）斑块的核心。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。我们目前的质谱和电子顺磁共振自旋捕获的证据表明，β-淀粉样蛋白，在水溶液中，片段，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的神经元具有神经毒性的浓度下，可以抑制氧化敏感的谷氨酰胺合成酶和肌酸激酶。此外，水杨酸羟基化测定表明，在无细胞孵育期间，β-淀粉样蛋白-（25-35）片段产生活性氧。这些结果制定成一个自由基为基础的统一假设β-淀粉样蛋白的神经毒性，并讨论了参考阿尔茨海默病的膜分子改变。
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.