Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit abeta -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 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.
McLaurin
J
J
Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine, University of Toronto, Toronto, Ontario, M5S 3H2, Canada. j.mclaurin@utoronto.ca
Golomb
R
R
Jurewicz
A
A
Antel
J P
JP
Fraser
P E
PE
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002942:Circular Dichroism; D006801:Humans; D007294:Inositol / Q000737:chemistry / Q000378:metabolism*; D008854:Microscopy, Electron; D008956:Models, Chemical; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D011487:Protein Conformation; D051381:Rats; D013237:Stereoisomerism
D016229:Amyloid beta-Peptides; D007294:Inositol