Butterfield D A, Hensley K, Harris M, Mattson M, Carney J
Department of Chemistry, University of Kentucky, Lexington 40506.
Biochem Biophys Res Commun. 1994 Apr 29;200(2):710-5. doi: 10.1006/bbrc.1994.1508.
We have previously reported (Hensley et al., Proc. Natl. Acad. Sci. USA (1994) in press) that beta-amyloid peptide fragments in aqueous media, in a metal-independent reaction, produce reactive peptide free radicals and reactive oxygen species. In contrast to the hours or days necessary to produce neurotoxicity and a detectable free radical for beta-amyloid, the extremely neurotoxic A beta(25-35) fragment of beta-amyloid peptide produces a detectable radical in minutes. We now report that A beta(25-35) is a potent lipoperoxidation initiator, as inferred from peptide-mediated reduction of nitroxyl stearate spin labels bound to rodent neocortical synaptosomal membranes. A beta(25-35) rapidly quenches the paramagnetism of membrane-bound 12-nitroxyl stearate spin probe deep within the lipid bilayer, but reacts poorly with the 5-nitroxyl isomer whose paramagnetic center is near the lipid/water interface. A beta(35-25), the non-neurotoxic reverse sequence of A beta(25-35), shows little proclivity to reduce either spin label. These findings are formulated into a "molecular shrapnel" model of neuronal membrane damage in Alzheimer's disease.
我们之前曾报道过（亨斯利等人，《美国国家科学院院刊》（1994年）待发表），在与金属无关的反应中，水性介质中的β-淀粉样肽片段会产生活性肽自由基和活性氧物种。与β-淀粉样蛋白产生神经毒性和可检测自由基所需的数小时或数天不同，β-淀粉样肽极具神经毒性的Aβ(25 - 35)片段在数分钟内就能产生可检测到的自由基。我们现在报道，从肽介导的与啮齿动物新皮质突触体膜结合的硬脂酸硝酰自旋标记物的还原情况推断，Aβ(25 - 35)是一种有效的脂质过氧化引发剂。Aβ(25 - 35)能迅速淬灭脂质双分子层深处与膜结合的12 - 硬脂酸硝酰自旋探针的顺磁性，但与顺磁性中心靠近脂质/水界面的5 - 硝酰异构体反应较差。Aβ(35 - 25)是Aβ(25 - 35)的非神经毒性反向序列，几乎没有还原任何一种自旋标记物的倾向。这些发现被纳入了阿尔茨海默病神经元膜损伤的“分子弹片”模型。
