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

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.