Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils

The formation of amyloid fibrils is a common biochemical characteristic that occurs in Alzheimer's disease and several other amyloidoses. The unifying structural feature of amyloid fibrils is their specific type of β-sheet conformation that differentiates these fibrils from the products of normal protein folding reactions. Here we describe the generation of an antibody domain, termed B10, that recognizes an amyloid-specific and conformationally defined epitope. This antibody domain was selected by phage-display from a recombinant library of camelid antibody domains. Surface plasmon resonance, immunoblots, and immunohistochemistry show that this antibody domain distinguishes Aβ amyloid fibrils from disaggregated Aβ peptide as well as from specific Aβ oligomers. The antibody domain possesses functional activity in preventing the formation of mature amyloid fibrils by stabilizing Aβ protofibrils. These data suggest possible applications of B10 in the detection of amyloid fibrils or in the modulation of their formation.

[1]  C. Almeida,et al.  Internalized Antibodies to the Aβ Domain of APP Reduce Neuronal Aβ and Protect against Synaptic Alterations*♦ , 2007, Journal of Biological Chemistry.

[2]  Chia-yu Lin,et al.  Toxic Human Islet Amyloid Polypeptide (h-IAPP) Oligomers Are Intracellular, and Vaccination to Induce Anti-Toxic Oligomer Antibodies Does Not Prevent h-IAPP–Induced β-Cell Apoptosis in h-IAPP Transgenic Mice , 2007, Diabetes.

[3]  W. Saeger,et al.  Interdisziplinäre Leitlinien zur Diagnostik und Therapie der extrazerebralen Amyloidosen , 2006, Medizinische Klinik.

[4]  N. Grigorieff,et al.  Quaternary structure of a mature amyloid fibril from Alzheimer's Abeta(1-40) peptide. , 2006, Journal of molecular biology.

[5]  E. Hund,et al.  [Interdisciplinary guidelines on diagnosis and treatment for extracerebral amyloidoses--published by the German Society of Amyloid Diseases (www.amyloid.de)]. , 2006, Deutsche medizinische Wochenschrift.

[6]  J. Lehmann,et al.  Alzheimer-like plaque formation by human macrophages is reduced by fibrillation inhibitors and lovastatin. , 2006, Journal of molecular biology.

[7]  H. Weiner,et al.  Immunology and immunotherapy of Alzheimer's disease , 2006, Nature Reviews Immunology.

[8]  Toru Iwaki,et al.  Surface plasmon resonance analysis for the screening of anti-prion compounds. , 2006, Biological & pharmaceutical bulletin.

[9]  L. Wyns,et al.  Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Roland Winter,et al.  Solvation-assisted pressure tuning of insulin fibrillation: from novel aggregation pathways to biotechnological applications. , 2006, Journal of molecular biology.

[11]  P. Westermark.  Aspects on human amyloid forms and their fibril polypeptides , 2005, The FEBS journal.

[12]  P. Hudson,et al.  Engineered antibody fragments and the rise of single domains , 2005, Nature Biotechnology.

[13]  M. Fändrich,et al.  The aggregation kinetics of Alzheimer's β‐amyloid peptide is controlled by stochastic nucleation , 2005, Protein science : a publication of the Protein Society.

[14]  Makoto Hashimoto,et al.  Effects of α-Synuclein Immunization in a Mouse Model of Parkinson’s Disease , 2005, Neuron.

[15]  M. Fändrich,et al.  FTIR reveals structural differences between native β‐sheet proteins and amyloid fibrils , 2004, Protein science : a publication of the Protein Society.

[16]  O. Antzutkin.  Amyloidosis of Alzheimer's Aβ peptides: solid‐state nuclear magnetic resonance, electron paramagnetic resonance, transmission electron microscopy, scanning transmission electron microscopy and atomic force microscopy studies , 2004, Magnetic resonance in chemistry : MRC.

[17]  C. Dobson.  Protein folding and misfolding , 2003, Nature.

[18]  P. Lansbury,et al.  Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. , 2003, Annual review of neuroscience.

[19]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Christopher M. Dobson,et al.  A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme , 2003, Nature.

[21]  Carl W. Cotman,et al.  Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis , 2003, Science.

[22]  J. Collinge,et al.  Monoclonal antibodies inhibit prion replication and delay the development of prion disease , 2003, Nature.

[23]  R. Nitsch,et al.  Generation of antibodies specific for β-amyloid by vaccination of patients with Alzheimer disease , 2002, Nature Medicine.

[24]  R. Wetzel,et al.  Conformational Abs recognizing a generic amyloid fibril epitope , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  F. Heppner,et al.  Prevention of Scrapie Pathogenesis by Transgenic Expression of Anti-Prion Protein Antibodies , 2001, Science.

[26]  Pauline M. Rudd,et al.  Antibodies inhibit prion propagation and clear cell cultures of prion infectivity , 2001, Nature.

[27]  Christopher M. Dobson,et al.  Amyloid fibrils from muscle myoglobin , 2001, Nature.

[28]  M. Schell,et al.  Antibody-mediated resolution of light chain-associated amyloid deposits. , 2000, The American journal of pathology.

[29]  S. Müller,et al.  Studies on the in Vitro Assembly of Aβ 1–40: Implications for the Search for Aβ Fibril Formation Inhibitors , 2000 .

[30]  P. Lansbury,et al.  Amyloid fibrillogenesis: themes and variations. , 2000, Current opinion in structural biology.

[31]  S. Muyldermans,et al.  Single domain antibodies: comparison of camel VH and camelised human VH domains. , 1999, Journal of immunological methods.

[32]  L. Wyns,et al.  Comparison of llama VH sequences from conventional and heavy chain antibodies. , 1997, Molecular immunology.

[33]  L. Serpell,et al.  Common core structure of amyloid fibrils by synchrotron X-ray diffraction. , 1997, Journal of molecular biology.

[34]  D. Walsh,et al.  Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. , 1997, The Journal of biological chemistry.

[35]  B. Solomon,et al.  Disaggregation of Alzheimer β-amyloid by site-directed mAb , 1997 .

[36]  B. Solomon,et al.  Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[37]  H. Rhode,et al.  Is the brush border membrane of the intestinal mucosa a generator of "chymosomes"? , 1994, Cellular and molecular biology.

[38]  H. Levine,et al.  Thioflavine T interaction with synthetic Alzheimer's disease β‐amyloid peptides: Detection of amyloid aggregation in solution , 1993, Protein science : a publication of the Protein Society.

[39]  A. Plückthun.  Mono‐ and Bivalent Antibody Fragments Produced in Escherichia coli: Engineering, Folding and Antigen Binding , 1992, Immunological reviews.

[40]  T. Clackson,et al.  Making antibody fragments using phage display libraries , 1991, Nature.

[41]  G. Winter,et al.  Phage antibodies: filamentous phage displaying antibody variable domains , 1990, Nature.

[42]  J. Pettegrew,et al.  Quantitative evaluation of congo red binding to amyloid-like proteins with a beta-pleated sheet conformation. , 1989, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[43]  E. Kremmer,et al.  Specific detection of his-tagged proteins with recombinant anti-His tag scFv-phosphatase or scFv-phage fusions. , 1997, BioTechniques.

[44]  Peter T. Lansbury,et al.  Observation of metastable Aβ amyloid protofibrils by atomic force microscopy , 1997 .

[45]  P. Lansbury,et al.  Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. , 1997, Annual review of biochemistry.

[46]  M. Skinner,et al.  The association of amyloid P-component (AP) with the amyloid fibril: an updated method for amyloid fibril protein isolation. , 1982, Preparative biochemistry.

[47]  C. Toniolo,et al.  Solid-state infrared absorption spectra and chain arrangement in some synthetic homooligopeptides in the intermolecularly hydrogen-bonded pleated-sheet beta-conformation. , 1977, Biopolymers.