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Amyloid-b(Ab) 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. | ỊFEBS Journal Modulation of amyloid-b aggregation and toxicity by inosose stereoisomers Mark Nitz1 Daniela Fenili2 3 Audrey A. Darabie2 Ling Wu2 Julian E. Cousins2 and JoAnne McLaurin2 3 1 Department of Chemistry University of Toronto Canada 2 Centre for Research in Neurodegenerative Diseases University of Toronto Canada 3 Department of Laboratory Medicine and Pathobiology University of Toronto Canada Keywords aggregation Alzheimer s disease amyloid fibrillogenesis inosose Correspondence J. McLaurin Centre for Research in Neurodegenerative Diseases University of Toronto 6 Queen s Park Crescent West Toronto ON Canada M5S 3H2 Fax 1 416 978 1878 Tel 1 416 978 1035 E-mail j.mclaurin@utoronto.ca Received 21 November 2007 revised 28 January 2008 accepted 5 February 2008 doi 10.1111 j.1742-4658.2008.06321.x Amyloid-b Ab 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 Ab aggregation and toxicity in vitro and in vivo. We report here the effects of inosose versus inositol stereoisomers on Ab fibrillogene-sis as determined using CD and fluorescence spectroscopy and negativestain 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-Ab interactions and identify both o o-inositol and epi-2-inosose as in vitro inhibitors of Ab aggregation. Inositol is a simple polyol with eight naturally occurring stereoisomers the most common of which are myo-inositol .
