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Title: Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice
Authors: Martins, Ivo Cristiano *
Kuperstein, Faina *
Wilkinson, Hannah
Maes, Elke
Vanbrabant, Mieke
Jonckheere, Wim
Van Gelder, Patrick
Hartmann, Dieter
D'Hooge, Rudi
De Strooper, Bart ×
Schymkowitz, Joost
Rousseau, Frederic #
Issue Date: Jan-2008
Publisher: Nature Publishing Group
Series Title: EMBO Journal vol:27 issue:1 pages:224-233
Abstract: Although soluble oligomeric and protofibrillar assemblies of Abeta-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Abeta-fibrils in the amyloid plaques remains controversial. A widely held view in the field suggests that the fibrillization reaction proceeds 'forward' in a near-irreversible manner from the monomeric Abeta peptide through toxic protofibrillar intermediates, which subsequently mature into biologically inert amyloid fibrils that are found in plaques. Here, we show that natural lipids destabilize and rapidly resolubilize mature Abeta amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Abeta but rather toward soluble amyloid protofibrils. We characterized these 'backward' Abeta protofibrils generated from mature Abeta fibers and compared them with previously identified 'forward' Abeta protofibrils obtained from the aggregation of fresh Abeta monomers. We find that backward protofibrils are biochemically and biophysically very similar to forward protofibrils: they consist of a wide range of molecular masses, are toxic to primary neurons and cause memory impairment and tau phosphorylation in mouse. In addition, they diffuse rapidly through the brain into areas relevant to AD. Our findings imply that amyloid plaques are potentially major sources of soluble toxic Abeta-aggregates that could readily be activated by exposure to biological lipids.
URI: 
ISSN: 0261-4189
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Biological Psychology
Molecular Genetics Section (-)
Switch Laboratory
Department of Human Genetics - miscellaneous
* (joint) first author
× corresponding author
# (joint) last author

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