title: Binding of human proteins to amyloid-β protofibrils.
abstract: The progressive neurodegeneration in Alzheimer's disease is believed to be linked to the presence of prefibrillar aggregates of the amyloid-β (Aβ) peptide in the brain. The exact role of these aggregates in the disease pathology is, however, still an open question. Any mechanism by which oligomeric Aβ may cause damage to neuronal cells must, in one way or another, involve interactions with other molecules. Here, we identify proteins in human serum and cerebrospinal fluid that bind to stable protofibrils formed by an engineered variant of Aβ42 (Aβ42CC). We find that the protofibrils attract a substantial number of protein binding partners. Many of the 101 identified proteins are involved in lipid transport and metabolism, the complement system, or in hemostasis. Binding of representative proteins from all of these groups with micromolar affinity was confirmed using surface plasmon resonance. In addition, binding of apolipoprotein E to the protofibrils with nanomolar affinity was demonstrated. We also find that aggregation of Aβ enhances protein binding, as lower amounts of proteins bind monomeric Aβ. Proteins that bind to Aβ protofibrils might contribute to biological effects in which these aggregates are involved. Our results therefore suggest that an improved understanding of the mechanisms by which Aβ causes cytotoxicity and neurodegeneration might be gained from studies carried out in biologically relevant matrices in which Aβ-binding proteins are present.
authors.affiliation: †Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences (SLU), Box 7015, SE-750 07 Uppsala, Sweden.
authors.forename: M Mahafuzur
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: ‡Department of Psychiatry and Neurochemistry, University of Gothenburg, SE-413 45 Göteborg, Sweden.|§UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: †Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences (SLU), Box 7015, SE-750 07 Uppsala, Sweden.
authors.forename: Christofer
authors.initials: C
authors.lastname: Lendel
authors.affiliation: †Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences (SLU), Box 7015, SE-750 07 Uppsala, Sweden.
authors.forename: Torleif
authors.initials: T
authors.lastname: Härd
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000737:chemistry* / Q000302:isolation & purification; D001798:Blood Proteins / Q000737:chemistry* / Q000302:isolation & purification; D002556:Cerebrospinal Fluid Proteins / Q000737:chemistry* / Q000302:isolation & purification; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D066329:Protein Aggregates; D011485:Protein Binding; D015202:Protein Engineering; D025941:Protein Interaction Mapping; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D001798:Blood Proteins; D002556:Cerebrospinal Fluid Proteins; D010446:Peptide Fragments; D066329:Protein Aggregates; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42)