Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid β peptide and inhibit Aβ-induced toxicity
Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid β peptide and inhibit Aβ-induced toxicity
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DOI：
10.1074/jbc.m906994199
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发表时间：
2000-06-16
影响因子：
4.8
通讯作者：
Fraser, PE
中科院分区：
文献类型：
--
作者：
McLaurin, J;Golomb, R;Fraser, PE
肌醇有8个立体异构体，其中4个是生理活性的，肌醇是大脑中含量最丰富的异构体，最近研究表明，表肌醇和镰状肌醇也存在。肌醇与Aβ42在体外形成稳定的小胶束。讨论了肌醇立体异构体与小的Aβ复合体相互作用和稳定的能力。圆二色谱表明，在Aβ42中，表型和胞型肌醇能够诱导从无规结构到β结构的结构转变。或者，没有一种立体异构体能够在Aβ40中诱导结构转变。电子显微镜显示，肌醇稳定Aβ42的小聚集体。我们证明，肌醇-Aβ相互作用产生的复合体对神经生长因子分化的PC-12细胞和原代人类神经元培养无毒。毒性的减弱是Aβ-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。肌醇立体异构体的使用使我们能够阐明Aβ和肌醇之间的重要构效关系。肌醇立体异构体是自然产生的分子，很容易穿过血脑屏障，可能是一种可行的治疗AD的方法，通过Aβ的络合作用和减弱Aβ的神经毒性作用。
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 A beta 42 in vitro to form a small stable micelle. The ability of inositol stereoisomers to interact with and stabilize small A beta 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 A beta 42. Alternatively, none of the stereoisomers were able to induce a structural transition in A beta 40. Electron microscopy demonstrated that inositol stabilizes small aggregates of A beta 42. We demonstrate that inositol-A beta 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 A beta-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 A beta 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 A beta and attenuation of A beta neurotoxic effects.