Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42

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A key event in Alzheimer's disease (AD) pathogenesis is the conversion of the peptide beta-amyloid (A beta) from its soluble monomeric form into various aggregated morphologies in the brain. Preventing aggregation of A beta is being actively pursued as a primary therapeutic strategy for treating AD. Trehalose, a simple disaccharide, has been shown to be effective in preventing the deactivation of numerous proteins and in protecting cells against stress. Here, we show that trehalose is also effective in inhibiting aggregation of A beta and reducing its cytotoxicity, although it shows differential effects toward A beta 40 and A beta 42. When co-incubated with A 40, trehalose inhibits formation of both fibrillar and oligomeric morphologies as determined by fluorescence staining and atomic force microscopy (AFM). However, when co-incubated with A beta 42, trehalose inhibits formation only of the fibrillar morphology, with significant oligomeric formation still present. When aggregated mixtures were incubated with SH-SY5Y cells, trehalose was shown to reduce the toxicity of A beta 40 mixtures, but not A beta 42. These results provide additional evidence that aggregation of A beta into soluble oligomeric forms is a pathological step in AD and that A beta 42 In particular is more susceptible to forming these toxic oligomers than A beta 40. These results also suggest that the use of trehalose, a highly soluble, low-priced sugar, as part of a potential therapeutic cocktail to control A peptide aggregation and toxicity warrants further study. (c) 2005 Elsevier Inc. All rights reserved.
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Issue Date
2005-10
Language
English
Article Type
Article
Keywords

AMYLOID-BETA-PEPTIDE; ATOMIC-FORCE MICROSCOPY; ANTIBODY LIGHT-CHAINS; ALZHEIMERS-DISEASE; IN-VITRO; A-BETA; MOUSE MODEL; FIBRIL FORMATION; PROTEIN; FIBRILLOGENESIS

Citation

NEUROBIOLOGY OF DISEASE, v.20, no.1, pp.74 - 81

ISSN
0969-9961
DOI
10.1016/j.nbd.2005.02.003
URI
http://hdl.handle.net/10203/25492
Appears in Collection
MS-Journal Papers(저널논문)
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