Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils

被引：384

作者：

Bieschke, Jan ^{[1
]}

Herbst, Martin ^{[1
,2
]}

Wiglenda, Thomas ^{[1
]}

Friedrich, Ralf P. ^{[1
]}

Boeddrich, Annett ^{[1
]}

Schiele, Franziska ^{[1
]}

Kleckers, Daniela ^{[1
]}

del Amo, Juan Miguel Lopez ^{[3
]}

Gruening, Bjoern A. ^{[4
]}

Wang, Qinwen ^{[5
]}

Schmidt, Michael R. ^{[1
]}

Lurz, Rudi ^{[6
]}

Anwyl, Roger ^{[5
]}

Schnoegl, Sigrid ^{[1
]}

Faendrich, Marcus ^{[7
]}

Frank, Ronald F. ^{[8
]}

Reif, Bernd ^{[3
,9
]}

Guenther, Stefan ^{[4
]}

Walsh, Dominic M. ^{[10
]}

Wanker, Erich E. ^{[1
]}

机构：

[1] Max Delbrueck Ctr Mol Med, Berlin, Germany

[2] Charite, Dept Neurol, D-13353 Berlin, Germany

[3] Helmholtz Ctr Infect Res, Braunschweig, Germany

[4] Univ Freiburg, Inst Pharmaceut Sci, D-79106 Freiburg, Germany

[5] Trinity Coll Dublin, Sch Med, Dept Physiol, Dublin, Ireland

[6] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

[7] Max Planck Res Unit Enzymol Prot Folding, Halle, Saale, Germany

[8] Helmholtz Ctr Infect Res, Dept Chem, Braunschweig, Germany

[9] Tech Univ Munich, Munich, Germany

[10] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Lab Neurodegenerat Res, Dublin, Ireland

来源：

NATURE CHEMICAL BIOLOGY | 2012年 / 8卷 / 01期

关键词：

LONG-TERM POTENTIATION; A-BETA; HUNTINGTONS-DISEASE; MISFOLDING DISEASES; COMMON MECHANISM; ALPHA-SYNUCLEIN; IN-VITRO; AGGREGATION; PEPTIDE; INHIBITORS;

D O I：

10.1038/nchembio.719

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Several lines of evidence indicate that prefibrillar assemblies of amyloid-beta (A beta) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of A beta fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in A beta peptides and stabilizes the self-assembly of seeding-competent, beta-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic A beta oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by A beta oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells.

引用

页码：93 / 101

页数：9

共 49 条

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