Article
- The EMBO Journal (2008) 27, 224 - 233
- doi:10.1038/sj.emboj.7601953
Published online: 6 December 2007
Subject Categories:
Lipids revert inert A
amyloid fibrils to neurotoxic protofibrils that affect learning in miceEMBO Open
Ivo Cristiano Martins1,5, Inna Kuperstein2,5, Hannah Wilkinson1, Elke Maes2, Mieke Vanbrabant2, Wim Jonckheere1, Patrick Van Gelder3, Dieter Hartmann2, Rudi D'Hooge4, Bart De Strooper2, Joost Schymkowitz1 and Frederic Rousseau1
- Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium
- Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium
- ULTR Laboratory, Department for Molecular and Cellular Interactions, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium
- Laboratory of Biological Psychology, KULeuven, Leuven, Belgium
Correspondence to:
Bart De Strooper, Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Herestraat 49, Leuven, Belgium. Tel.: +3216346227; Fax: +3216347181; E-mail: bart.destrooper@med.kuleuven.be
Joost Schymkowitz, Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussel 1050, Belgium. Tel.: +3226291425; Fax: +3226291963; E-mail: joost.schymkowitz@vub.ac.be
Frederic Rousseau, Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussel 1050, Belgium. Tel.: +3226291425; Fax: +3226291963; E-mail: frederic.rousseau@vub.ac.be
5These authors contributed equally to this work
Received 14 July 2007; Accepted 19 November 2007
Abstract
Although soluble oligomeric and protofibrillar assemblies of A
-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature A-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 A 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 A amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric A but rather toward soluble amyloid protofibrils. We characterized these 'backward' A protofibrils generated from mature A fibers and compared them with previously identified 'forward' A protofibrils obtained from the aggregation of fresh A 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 A-aggregates that could readily be activated by exposure to biological lipids.
Keywords:
- Alzheimer's disease,
- amyloid fibril,
- amyloidosis,
- lipid
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