Inositol stereoisomers stabilize an oligomeric aggregate of alzheimer amyloid β peptide and inhibit Aβ-induced toxicity

Abstract

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 Aβ42 in vitro to form a small stable micelle. The ability of inositol stereoisomers to interact with and stabilize small Aβ 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 β-structure in Aβ42. Alternatively, none of the stereoisomers were able to induce a structural transition in Aβ40. Electron microscopy demonstrated that inositol stabilizes small aggregates of Aβ42. We demonstrate that inositol-Aβ 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 Aβ-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 Aβ 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 Aβ and attenuation of Aβ neurotoxic effects.