McLaurin J, Golomb R, Jurewicz A, Antel J P, Fraser P E
Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine, University of Toronto, Toronto, Ontario, M5S 3H2, Canada.
J Biol Chem. 2000 Jun 16;275(24):18495-502. doi: 10.1074/jbc.M906994199.
Inositol has 8 stereoisomers, four of which are physiologically active. myo-Inositol is the most abundant isomer in the brain and more recently shown that epi- and scyllo-inositol are also present. myo-Inositol complexes with Abeta42 in vitro to form a small stable micelle. The ability of inositol stereoisomers to interact with and stabilize small Abeta complexes was addressed. Circular dichroism spectroscopy demonstrated that epi- and scyllo- but not chiro-inositol were able to induce a structural transition from random to beta-structure in Abeta42. Alternatively, none of the stereoisomers were able to induce a structural transition in Abeta40. Electron microscopy demonstrated that inositol stabilizes small aggregates of Abeta42. We demonstrate that inositol-Abeta interactions result in a complex that is non-toxic to nerve growth factor-differentiated PC-12 cells and primary human neuronal cultures. The attenuation of toxicity is the result of Abeta-inositol interaction, as inositol uptake inhibitors had no effect on neuronal survival. The use of inositol stereoisomers allowed us to elucidate an important structure-activity relationship between Abeta and inositol. Inositol stereoisomers are naturally occurring molecules that readily cross the blood-brain barrier and may represent a viable treatment for AD through the complexation of Abeta and attenuation of Abeta neurotoxic effects.
肌醇有8种立体异构体，其中4种具有生理活性。肌醇是大脑中含量最丰富的异构体，最近研究表明表肌醇和 scyllo-肌醇也存在。肌醇在体外与β-淀粉样蛋白42（Aβ42）结合形成一个小的稳定微团。研究了肌醇立体异构体与小Aβ复合物相互作用并使其稳定的能力。圆二色光谱表明，表肌醇和scyllo-肌醇而非手性肌醇能够诱导Aβ42从无规结构向β结构转变。另外，没有一种立体异构体能够诱导Aβ40发生结构转变。电子显微镜显示肌醇可稳定Aβ42的小聚集体。我们证明肌醇与Aβ的相互作用产生一种对神经生长因子分化的PC-12细胞和原代人神经元培养物无毒的复合物。毒性的减弱是Aβ与肌醇相互作用的结果，因为肌醇摄取抑制剂对神经元存活没有影响。使用肌醇立体异构体使我们能够阐明Aβ与肌醇之间重要的构效关系。肌醇立体异构体是天然存在的分子，能够轻易穿过血脑屏障，可能通过Aβ的络合作用和减弱Aβ神经毒性作用而成为治疗阿尔茨海默病（AD）的一种可行疗法。
