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. <i>myo</i>-Inositol is the most abundant isomer in the brain and more recently shown that <i>epi</i>- and<i>scyllo</i>-inositol are also present. <i>myo</i>-Inositol complexes with Aβ42 <i>in vitro</i> 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 <i>epi</i>- and <i>scyllo</i>- but not <i>chiro</i>-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.