Modulation of amyloid-beta aggregation and toxicity by inosose stereoisomers.
Amyloid-beta (Abeta) aggregation and amyloid formation are key pathological features of Alzheimer's disease, and are considered to be two of the major contributing factors to neurodegeneration and dementia. Identification of small molecule inhibitors that are orally available, have low toxicity and high central nervous system bioavailability is one approach to the potential development of a disease-modifying treatment for Alzheimer's disease. We have previously identified inositol stereoisomers as exhibiting stereospecific inhibition of Abeta aggregation and toxicity in vitro and in vivo. We report here the effects of inosose versus inositol stereoisomers on Abeta fibrillogenesis as determined using CD and fluorescence spectroscopy and negative-stain electron microscopy. The inososes differ from inositols by the oxidation of one of the hydroxyl groups to a ketone. These molecules help in the further elucidation of the structure-activity relationships of inositol-Abeta interactions and identify both allo-inositol and epi-2-inosose as in vitro inhibitors of Abeta aggregation.
Nitz
Mark
M
Department of Chemistry, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario, Canada.
Fenili
Daniela
D
Darabie
Audrey A
AA
Wu
Ling
L
Cousins
Julian E
JE
McLaurin
JoAnne
J
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D007294:Inositol / Q000031:analogs & derivatives* / Q000737:chemistry; D008854:Microscopy, Electron; D015394:Molecular Structure; D016716:PC12 Cells; D051381:Rats; D013237:Stereoisomerism; D027981:Symporters / Q000378:metabolism
D016229:Amyloid beta-Peptides; D027981:Symporters; C002183:inosose; D007294:Inositol