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

Habicht, Gernot; Haupt, Christian; Friedrich, Ralf P.; Hortschansky, Peter; Sachse, Carsten; Meinhardt, Jessica; Wieligmann, Karin; Gellermann, Gerald P.; Brodhun, Michael; Götz, Jürgen; Kj, Halbhuber; Röcken, Christoph; Horn, Uwe; Fändrich, Marcus

doi:10.1073/pnas.0703793104

Cited by 205 publications

(263 citation statements)

References 46 publications

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“…Moreover, the antiparallel b-sheet organization of Ab(1-40) oligomers has been previously suggested in Habicht et al [19] and is in agreement with previous structural studies carried out on Ab(1-42) oligomers [20,21] as well as on other proteins forming oligomers like b 2 -microglobulin [53] and PrP (prion related protein) peptide [PrP-(82-146)] [54]. Additionally, Ab oligomers are recognized by the A11 antibody.…”

Section: Discussionsupporting

confidence: 90%

“…Our observations suggest that self-assembling of Ab(1-40) from oligomers to fibrils involves the central (aa [17][18][19][20][21][22][23][24] and C-terminal parts (aa 30-40) of the peptide (Fig. 3).…”

Section: Discussionmentioning

confidence: 71%

“…Nevertheless, infrared spectroscopy on Ab(1-40) [19] and [20,21] oligomers shows an antiparallel b-sheet organization.…”

Section: Introductionmentioning

confidence: 98%

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Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

137

119

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Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid beta peptide (Ab) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared spectroscopy to provide structural information on the entire aggregation pathway of Ab(1-40), starting from monomeric Ab to the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition from antiparallel to parallel b-sheet. These structural changes are described in terms of H-bonding rupture/formation, b-strands reorientation and b-sheet elongation. As antiparallel b-sheet structure is also observed for other amyloidogenic proteins forming oligomers, reorganization of the b-sheet implicating a reorientation of b-strands could be a generic mechanism determining the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 71%

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Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

137

119

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“…From Ref. [154]. Therefore, KW1AP and B10AP both prevent the formation of mature Ab fibrils, either by inducing the accumulation of non-fibrillar aggregates or by stabilising the protofibrils respectively.…”

Section: Ab Peptide and Alzheimer's Diseasementioning

confidence: 85%

“…monomers, oligomers and/or fibrils), have been generated and characterised in detail; they are referred to as B10 [154], KW1 [155], V31-1 [152], PrioAD12 and PrioAD13 [127] and ni3A [156].…”

Section: Generation Of Ab Specific Nanobodiesmentioning

confidence: 99%

Camelid single-domain antibody fragments: Uses and prospects to investigate protein misfolding and aggregation, and to treat diseases associated with these phenomena

2015

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Keywords:Variable domain of heavy-chain antibody Inhibition of protein misfolding and aggregation Protein misfolding diseases Amyloidoses V H H Nanobody a b s t r a c tThe deposition of misfolded peptides and proteins in the form of amyloid fibrils is the hallmark of nearly fifty medical disorders, including Alzheimer's disease, Parkinson's disease, prion diseases and type II diabetes. These disorders, referred to as amyloidoses, generally become apparent late in life. Their psycho-sociological and economic incidence in western societies will be therefore considerable in the coming decades due to the ageing of the population. Neither preventing nor curative treatments are available yet. These disorders constitute therefore a medical challenge of great importance. Thus, an extensive research is being carried out to understand, at the molecular level, (i) how amyloidogenic proteins misfold and convert from their soluble form into amyloid fibrils, and (ii) how these aggregates or some of their oligomeric precursor species are toxic. The formation of amyloid fibrils proceeds through a complex nucleation/polymerisation mechanism with the formation of various species, including small oligomers. In this review, we focus on how V H Hs or nanobodies, the antigen-binding domains of camelid heavy-chain antibodies, are being increasingly used to characterise each of the species formed on the pathway of fibril formation in terms of structure, stability, kinetics of formation and toxicity. We first introduce the characteristic features of nanobodies compared to those of conventional antibody fragments. Thereafter, we discuss how nanobodies, due to their unique properties, are used as probes to dissect the molecular mechanisms of misfolding and aggregation of six proteins associated with diseases, i.e. human lysozyme, b2-microglobulin, a-synuclein, prion, polyadenylate binding protein nuclear 1 and amyloid b-peptide. A brief general presentation of each disease and the associated peptide/protein is also provided. In addition, we discuss how nanobodies could be used as early diagnostic tools and as novel strategies to treat diseases associated with protein misfolding and aggregation.© 2015 Elsevier B.V. and Societe Française de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.Abbreviations: Ab, antibody; Ab, amyloid b-peptide; AD, Alzheimer's disease; ANS, anilino naphthalene-sulfonic acid; AP, alkaline phosphatase; APP, amyloid precursor protein; aSyn, a-synuclein; b2m, b2-microglobulin; BBB, bloodebrain barrier; CDR, complementarity determining region; C m , concentration of mid-denaturation; CR, Congo red; CSF, cerebrospinal fluid; DN6b2m, a truncated form of b2m lacking the six N-terminal amino acids; DLS, dynamic light scattering; DRA, dialysis-related amyloidosis; FR, framework; FTIR, Fourier transform infrared spectroscopy; Fv, variable fragment made of the VH and VL domains of conventional antibodies; GFP, green fluorescent protein; HCAb, heavy-chain antibody; H/D, hydrogen/deuterium; HSQC, heteronuclear s...

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Imaging of Misfolded Proteins

LeVine

2010

Protein Misfolding Diseases

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

Cited by 205 publications

References 46 publications

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Camelid single-domain antibody fragments: Uses and prospects to investigate protein misfolding and aggregation, and to treat diseases associated with these phenomena

Imaging of Misfolded Proteins

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