Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice
Identifieur interne : 001638 ( Istex/Corpus ); précédent : 001637; suivant : 001639Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice
Auteurs : Ivo Cristiano Martins ; Inna Kuperstein ; Hannah Wilkinson ; Elke Maes ; Mieke Vanbrabant ; Wim Jonckheere ; Patrick Van Gelder ; Dieter Hartmann ; Rudi D'Hooge ; Bart De Strooper ; Joost Schymkowitz ; Frederic RousseauSource :
- The EMBO Journal [ 0261-4189 ] ; 2008-01-09.
Abstract
Although soluble oligomeric and protofibrillar assemblies of Aβ‐amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ‐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 Aβ 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 Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward’ Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward’ Aβ protofibrils obtained from the aggregation of fresh Aβ 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 Aβ‐aggregates that could readily be activated by exposure to biological lipids.
Url:
DOI: 10.1038/sj.emboj.7601953
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Belgium</mods:affiliation></affiliation></author><author><name sortKey="Maes, Elke" sort="Maes, Elke" uniqKey="Maes E" first="Elke" last="Maes">Elke Maes</name><affiliation><mods:affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Vanbrabant, Mieke" sort="Vanbrabant, Mieke" uniqKey="Vanbrabant M" first="Mieke" last="Vanbrabant">Mieke Vanbrabant</name><affiliation><mods:affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Jonckheere, Wim" sort="Jonckheere, Wim" uniqKey="Jonckheere W" first="Wim" last="Jonckheere">Wim Jonckheere</name><affiliation><mods:affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Van Gelder, Patrick" sort="Van Gelder, Patrick" uniqKey="Van Gelder P" first="Patrick" last="Van Gelder">Patrick Van Gelder</name><affiliation><mods:affiliation>ULTR Laboratory, Department for Molecular and Cellular Interactions, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Hartmann, Dieter" sort="Hartmann, Dieter" uniqKey="Hartmann D" first="Dieter" last="Hartmann">Dieter Hartmann</name><affiliation><mods:affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="D Hooge, Rudi" sort="D Hooge, Rudi" uniqKey="D Hooge R" first="Rudi" last="D'Hooge">Rudi D'Hooge</name><affiliation><mods:affiliation>Laboratory of Biological Psychology, Leuven, KULeuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="De Strooper, Bart" sort="De Strooper, Bart" uniqKey="De Strooper B" first="Bart" last="De Strooper">Bart De Strooper</name><affiliation><mods:affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Schymkowitz, Joost" sort="Schymkowitz, Joost" uniqKey="Schymkowitz J" first="Joost" last="Schymkowitz">Joost Schymkowitz</name><affiliation><mods:affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Rousseau, Frederic" sort="Rousseau, Frederic" uniqKey="Rousseau F" first="Frederic" last="Rousseau">Frederic Rousseau</name><affiliation><mods:affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">The EMBO Journal</title><idno type="ISSN">0261-4189</idno><idno type="eISSN">1460-2075</idno><imprint><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2008-01-09">2008-01-09</date><biblScope unit="volume">27</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="224">224</biblScope><biblScope unit="page" to="233">233</biblScope></imprint><idno type="ISSN">0261-4189</idno></series><idno type="istex">070DFF7B1C2B56E89F917DC0F83C5172011662D2</idno><idno type="DOI">10.1038/sj.emboj.7601953</idno><idno type="ArticleID">EMBJ7601953</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0261-4189</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Although soluble oligomeric and protofibrillar assemblies of Aβ‐amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ‐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 Aβ 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 Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward’ Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward’ Aβ protofibrils obtained from the aggregation of fresh Aβ 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 Aβ‐aggregates that could readily be activated by exposure to biological lipids.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Ivo Cristiano Martins</name><affiliations><json:string>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</json:string></affiliations></json:item><json:item><name>Inna Kuperstein</name><affiliations><json:string>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Hannah Wilkinson</name><affiliations><json:string>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</json:string></affiliations></json:item><json:item><name>Elke Maes</name><affiliations><json:string>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Mieke Vanbrabant</name><affiliations><json:string>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Wim Jonckheere</name><affiliations><json:string>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</json:string></affiliations></json:item><json:item><name>Patrick Van Gelder</name><affiliations><json:string>ULTR Laboratory, Department for Molecular and Cellular Interactions, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</json:string></affiliations></json:item><json:item><name>Dieter Hartmann</name><affiliations><json:string>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Rudi D'Hooge</name><affiliations><json:string>Laboratory of Biological Psychology, Leuven, KULeuven, Belgium</json:string></affiliations></json:item><json:item><name>Bart De Strooper</name><affiliations><json:string>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Joost Schymkowitz</name><affiliations><json:string>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</json:string></affiliations></json:item><json:item><name>Frederic Rousseau</name><affiliations><json:string>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Alzheimer's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>amyloid fibril</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>amyloidosis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>lipid</value></json:item></subject><articleId><json:string>EMBJ7601953</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Although soluble oligomeric and protofibrillar assemblies of Aβ‐amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ‐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 Aβ 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 Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward’ Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward’ Aβ protofibrils obtained from the aggregation of fresh Aβ 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 Aβ‐aggregates that could readily be activated by exposure to biological lipids.</abstract><qualityIndicators><score>7.4</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595 x 794 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>4</keywordCount><abstractCharCount>1436</abstractCharCount><pdfWordCount>7540</pdfWordCount><pdfCharCount>47895</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>200</abstractWordCount></qualityIndicators><title>Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice</title><genre><json:string>article</json:string></genre><host><volume>27</volume><publisherId><json:string>EMBJ</json:string></publisherId><pages><total>10</total><last>233</last><first>224</first></pages><issn><json:string>0261-4189</json:string></issn><issue>1</issue><subject><json:item><value>Molecular Biology of 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mice</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><availability status="free"><p>Open Access</p></availability><date>2008</date></publicationStmt><notesStmt><note>Supplementary Information</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice</title><author xml:id="author-1"><persName><forename type="first">Ivo Cristiano</forename><surname>Martins</surname></persName><note type="biography">These authors contributed equally to this work</note><affiliation>These authors contributed equally to this work</affiliation><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation></author><author xml:id="author-2"><persName><forename type="first">Inna</forename><surname>Kuperstein</surname></persName><note type="biography">These authors contributed equally to this work</note><affiliation>These authors contributed equally to this work</affiliation><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation></author><author xml:id="author-3"><persName><forename type="first">Hannah</forename><surname>Wilkinson</surname></persName><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation></author><author xml:id="author-4"><persName><forename type="first">Elke</forename><surname>Maes</surname></persName><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation></author><author xml:id="author-5"><persName><forename type="first">Mieke</forename><surname>Vanbrabant</surname></persName><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation></author><author xml:id="author-6"><persName><forename type="first">Wim</forename><surname>Jonckheere</surname></persName><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation></author><author xml:id="author-7"><persName><forename type="first">Patrick</forename><surname>Van Gelder</surname></persName><affiliation>ULTR Laboratory, Department for Molecular and Cellular Interactions, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation></author><author xml:id="author-8"><persName><forename type="first">Dieter</forename><surname>Hartmann</surname></persName><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation></author><author xml:id="author-9"><persName><forename type="first">Rudi</forename><surname>D'Hooge</surname></persName><affiliation>Laboratory of Biological Psychology, Leuven, KULeuven, Belgium</affiliation></author><author xml:id="author-10"><persName><forename type="first">Bart</forename><surname>De Strooper</surname></persName><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation></author><author xml:id="author-11"><persName><forename type="first">Joost</forename><surname>Schymkowitz</surname></persName><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation></author><author xml:id="author-12"><persName><forename type="first">Frederic</forename><surname>Rousseau</surname></persName><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation></author></analytic><monogr><title level="j">The EMBO Journal</title><idno type="pISSN">0261-4189</idno><idno type="eISSN">1460-2075</idno><idno type="DOI">10.1002/(ISSN)1460-2075</idno><imprint><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2008-01-09"></date><biblScope unit="volume">27</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="224">224</biblScope><biblScope unit="page" to="233">233</biblScope></imprint></monogr><idno type="istex">070DFF7B1C2B56E89F917DC0F83C5172011662D2</idno><idno type="DOI">10.1038/sj.emboj.7601953</idno><idno type="ArticleID">EMBJ7601953</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Although soluble oligomeric and protofibrillar assemblies of Aβ‐amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ‐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 Aβ 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 Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward’ Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward’ Aβ protofibrils obtained from the aggregation of fresh Aβ 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 Aβ‐aggregates that could readily be activated by exposure to biological lipids.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Alzheimer's disease</term></item><item><term>amyloid fibril</term></item><item><term>amyloidosis</term></item><item><term>lipid</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>index-terms</head><item><term>Molecular Biology of Disease</term></item><item><term>Structural Biology</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2007-07-14">Received</change><change when="2007-11-19">Registration</change><change when="2008-01-09">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/070DFF7B1C2B56E89F917DC0F83C5172011662D2/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component type="serialArticle" version="2.0" xml:lang="en" xml:id="embj7601953"><header><publicationMeta level="product"><publisherInfo><publisherName>John Wiley & Sons, Ltd</publisherName><publisherLoc>Chichester, UK</publisherLoc></publisherInfo><doi>10.1002/(ISSN)1460-2075</doi><issn type="print">0261-4189</issn><issn type="electronic">1460-2075</issn><idGroup><id type="product" value="EMBJ"></id></idGroup><titleGroup><title type="main" sort="THE EMBO JOURNAL">The EMBO Journal</title></titleGroup></publicationMeta><publicationMeta level="part" position="10"><doi>10.1002/emboj.v27.1</doi><copyright ownership="publisher">Copyright © 2013 Wiley Periodicals, Inc</copyright><numberingGroup><numbering type="journalVolume" number="27">27</numbering><numbering type="journalIssue">1</numbering></numberingGroup><coverDate startDate="2008-01-09">January 9, 2008</coverDate></publicationMeta><publicationMeta level="unit" position="210" accessType="open" type="article" status="forIssue"><doi>10.1038/sj.emboj.7601953</doi><idGroup><id type="unit" value="EMBJ7601953"></id></idGroup><countGroup><count type="pageTotal" number="10"></count></countGroup><titleGroup><title type="articleCategory">Article</title><title type="tocHeading1">Article</title></titleGroup><copyright ownership="thirdParty">Copyright © 2008 European Molecular Biology Organization</copyright><legalStatement type="creativeCommonsBy-nc-nd"><p>This is an open access article under the terms of the <url href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Attribution‐NonCommercial‐NoDerivs</url> License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.</p></legalStatement><eventGroup><event type="manuscriptReceived" date="2007-07-14"></event><event type="manuscriptAccepted" date="2007-11-19"></event><event type="publishedOnlineEarlyUnpaginated" date="2007-12-06"></event><event type="publishedOnlineFinalForm" date="2008-01-09"></event><event type="xmlConverted" agent="SPi Global Converter_TO_WileyML3Gv2.0 version:1.0; WileyML 3G Packaging Tool v1.0" date="2013-10-18"></event><event type="xmlCorrected" agent="Wiley-VCH" date="2013-11-19"></event><event type="firstOnline" date="2007-12-06"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-11-04"></event></eventGroup><numberingGroup><numbering type="pageFirst">224</numbering><numbering type="pageLast">233</numbering></numberingGroup><correspondenceTo>Corresponding authors: 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: <email>bart.destrooper@med.kuleuven.be</email> Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussel 1050, Belgium. Tel.: +3226291425; Fax: +3226291963; E-mail: <email>joost.schymkowitz@vub.ac.be</email> or E-mail: <email>frederic.rousseau@vub.ac.be</email></correspondenceTo><subjectInfo><subject href="http://psi.embo.org/14602075/subject/17">Molecular Biology of Disease</subject><subject href="http://psi.embo.org/14602075/subject/19">Structural Biology</subject></subjectInfo><attributeValueGroup><attributeValue element="note" attribute="type" value="equal"></attributeValue></attributeValueGroup><linkGroup><link type="toTypesetVersion" href="file:EMBJ.EMBJ7601953.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice</title><title type="short">Reversal of inert amyloid to neurotoxic species</title></titleGroup><creators><creator creatorRole="author" xml:id="embj7601953-cr-0001" affiliationRef="#embj7601953-aff-0001" noteRef="#embj7601953-note-0001"><personName><givenNames>Ivo Cristiano</givenNames><familyName>Martins</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0002" affiliationRef="#embj7601953-aff-0002" noteRef="#embj7601953-note-0001"><personName><givenNames>Inna</givenNames><familyName>Kuperstein</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0003" affiliationRef="#embj7601953-aff-0001"><personName><givenNames>Hannah</givenNames><familyName>Wilkinson</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0004" affiliationRef="#embj7601953-aff-0002"><personName><givenNames>Elke</givenNames><familyName>Maes</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0005" affiliationRef="#embj7601953-aff-0002"><personName><givenNames>Mieke</givenNames><familyName>Vanbrabant</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0006" affiliationRef="#embj7601953-aff-0001"><personName><givenNames>Wim</givenNames><familyName>Jonckheere</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0007" affiliationRef="#embj7601953-aff-0003"><personName><givenNames>Patrick</givenNames><familyName>Van Gelder</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0008" affiliationRef="#embj7601953-aff-0002"><personName><givenNames>Dieter</givenNames><familyName>Hartmann</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0009" affiliationRef="#embj7601953-aff-0004"><personName><givenNames>Rudi</givenNames><familyName>D'Hooge</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0010" affiliationRef="#embj7601953-aff-0002" corresponding="yes"><personName><givenNames>Bart</givenNames><familyName>De Strooper</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0011" affiliationRef="#embj7601953-aff-0001" corresponding="yes"><personName><givenNames>Joost</givenNames><familyName>Schymkowitz</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601953-cr-0012" affiliationRef="#embj7601953-aff-0001" corresponding="yes"><personName><givenNames>Frederic</givenNames><familyName>Rousseau</familyName></personName></creator></creators><affiliationGroup><affiliation countryCode="BE" type="organization" xml:id="embj7601953-aff-0001"><orgName>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB)</orgName><address><city>Brussel</city><country>Belgium</country></address></affiliation><affiliation countryCode="BE" type="organization" xml:id="embj7601953-aff-0002"><orgName>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven</orgName><address><city>Leuven</city><country>Belgium</country></address></affiliation><affiliation countryCode="BE" type="organization" xml:id="embj7601953-aff-0003"><orgName>ULTR Laboratory, Department for Molecular and Cellular Interactions, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB)</orgName><address><city>Brussel</city><country>Belgium</country></address></affiliation><affiliation countryCode="BE" type="organization" xml:id="embj7601953-aff-0004"><orgName>Laboratory of Biological Psychology</orgName><address><city>KULeuven</city><countryPart>Leuven</countryPart><country>Belgium</country></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="embj7601953-kwd-0001">Alzheimer's disease</keyword><keyword xml:id="embj7601953-kwd-0002">amyloid fibril</keyword><keyword xml:id="embj7601953-kwd-0003">amyloidosis</keyword><keyword xml:id="embj7601953-kwd-0004">lipid</keyword></keywordGroup><supportingInformation><supportingInfoItem xml:id="embj7601953-sup-0001"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:02614189:media:embj7601953:embj7601953-sup-0001"></mediaResource><caption><p>Supplementary Information</p></caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main"><p>Although soluble oligomeric and protofibrillar assemblies of Aβ‐amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ‐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 Aβ 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 Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward’ Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward’ Aβ protofibrils obtained from the aggregation of fresh Aβ 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 Aβ‐aggregates that could readily be activated by exposure to biological lipids.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="embj7601953-note-0001" type="equal">These authors contributed equally to this work</note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Reversal of inert amyloid to neurotoxic species</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice</title></titleInfo><name type="personal"><namePart type="given">Ivo Cristiano</namePart><namePart type="family">Martins</namePart><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation><description>These authors contributed equally to this work</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Inna</namePart><namePart type="family">Kuperstein</namePart><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation><description>These authors contributed equally to this work</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hannah</namePart><namePart type="family">Wilkinson</namePart><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elke</namePart><namePart type="family">Maes</namePart><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mieke</namePart><namePart type="family">Vanbrabant</namePart><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wim</namePart><namePart type="family">Jonckheere</namePart><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrick</namePart><namePart type="family">Van Gelder</namePart><affiliation>ULTR Laboratory, Department for Molecular and Cellular Interactions, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dieter</namePart><namePart type="family">Hartmann</namePart><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rudi</namePart><namePart type="family">D'Hooge</namePart><affiliation>Laboratory of Biological Psychology, Leuven, KULeuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bart</namePart><namePart type="family">De Strooper</namePart><affiliation>Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium</affiliation><description>Correspondence: Corresponding authors: 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: Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussel 1050, Belgium. Tel.: +3226291425; Fax: +3226291963; E-mail: or E-mail: </description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Joost</namePart><namePart type="family">Schymkowitz</namePart><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation><description>Correspondence: Corresponding authors: 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: Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussel 1050, Belgium. Tel.: +3226291425; Fax: +3226291963; E-mail: or E-mail: </description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Frederic</namePart><namePart type="family">Rousseau</namePart><affiliation>Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium</affiliation><description>Correspondence: Corresponding authors: 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: Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussel 1050, Belgium. Tel.: +3226291425; Fax: +3226291963; E-mail: or E-mail: </description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>John Wiley & Sons, Ltd</publisher><place><placeTerm type="text">Chichester, UK</placeTerm></place><dateIssued encoding="w3cdtf">2008-01-09</dateIssued><dateCaptured encoding="w3cdtf">2007-07-14</dateCaptured><dateValid encoding="w3cdtf">2007-11-19</dateValid><copyrightDate encoding="w3cdtf">2008</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Although soluble oligomeric and protofibrillar assemblies of Aβ‐amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ‐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 Aβ 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 Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward’ Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward’ Aβ protofibrils obtained from the aggregation of fresh Aβ 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 Aβ‐aggregates that could readily be activated by exposure to biological lipids.</abstract><note type="additional physical form">Supplementary Information</note><subject><genre>keywords</genre><topic>Alzheimer's disease</topic><topic>amyloid fibril</topic><topic>amyloidosis</topic><topic>lipid</topic></subject><relatedItem type="host"><titleInfo><title>The EMBO Journal</title></titleInfo><genre type="journal">journal</genre><subject><genre>index-terms</genre><topic authorityURI="http://psi.embo.org/14602075/subject/17">Molecular Biology of Disease</topic><topic authorityURI="http://psi.embo.org/14602075/subject/19">Structural Biology</topic></subject><subject><genre>article-category</genre><topic>Article</topic></subject><identifier type="ISSN">0261-4189</identifier><identifier type="eISSN">1460-2075</identifier><identifier type="DOI">10.1002/(ISSN)1460-2075</identifier><identifier type="PublisherID">EMBJ</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>27</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>224</start><end>233</end><total>10</total></extent></part></relatedItem><identifier type="istex">070DFF7B1C2B56E89F917DC0F83C5172011662D2</identifier><identifier type="DOI">10.1038/sj.emboj.7601953</identifier><identifier type="ArticleID">EMBJ7601953</identifier><accessCondition type="use and reproduction" contentType="creativeCommonsBy-nc-nd">This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>John Wiley & Sons, Ltd</recordOrigin></recordInfo></mods></metadata><enrichments><json:item><type>multicat</type><uri>https://api.istex.fr/document/070DFF7B1C2B56E89F917DC0F83C5172011662D2/enrichments/multicat</uri></json:item></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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