A{beta}42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete A{beta}42 Species.

Details

Ressource 1Request a copy Sous embargo indéterminé.
State: Public
Version: author
Serval ID
serval:BIB_1734901564D2
Type
Article: article from journal or magazin.
Collection
Publications
Title
A{beta}42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete A{beta}42 Species.
Journal
Journal of Biological Chemistry
Author(s)
Jan A., Adolfsson O., Allaman I., Buccarello A.L., Magistretti P.J., Pfeifer A., Muhs A., Lashuel H.A.
ISSN
1083-351X[electronic], 0021-9258[linking]
Publication state
Published
Issued date
2011
Peer-reviewed
Oui
Volume
286
Number
10
Pages
8585-8596
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
The identification of toxic Aβ species and/or the process of their formation is crucial for understanding the mechanism(s) of Aβ neurotoxicity in Alzheimer disease and also for the development of effective diagnostic and therapeutic interventions. To elucidate the structural basis of Aβ toxicity, we developed different procedures to isolate Aβ species of defined size and morphology distribution, and we investigated their toxicity in different cell lines and primary neurons. We observed that crude Aβ42 preparations, containing a monomeric and heterogeneous mixture of Aβ42 oligomers, were more toxic than purified monomeric, protofibrillar fractions, or fibrils. The toxicity of protofibrils was directly linked to their interactions with monomeric Aβ42 and strongly dependent on their ability to convert into amyloid fibrils. Subfractionation of protofibrils diminished their fibrillization and toxicity, whereas reintroduction of monomeric Aβ42 into purified protofibril fractions restored amyloid formation and enhanced their toxicity. Selective removal of monomeric Aβ42 from these preparations, using insulin-degrading enzyme, reversed the toxicity of Aβ42 protofibrils. Together, our findings demonstrate that Aβ42 toxicity is not linked to specific prefibrillar aggregate(s) but rather to the ability of these species to grow and undergo fibril formation, which depends on the presence of monomeric Aβ42. These findings contribute significantly to the understanding of amyloid formation and toxicity in Alzheimer disease, provide novel insight into mechanisms of Aβ protofibril toxicity, and important implications for designing anti-amyloid therapies.
Pubmed
Open Access
Yes
Create date
11/03/2011 15:57
Last modification date
20/08/2019 13:47
Usage data