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. Stabilization of a beta-hairpin in monomeric Alzheimer's amyloid-beta peptide inhibits amyloid formation. Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5099-104. PubMed.

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  1. Grönwall et al. (2007) recently applied phage-display techniques to identify affibody ligands that efficiently capture Aβ peptides from human plasma and serum. In the present paper by Hoyer et al., one of these phage-selected affibodies, Zab3, is shown to form a disulfide cross-linked dimer that binds monomeric Aβ(1-40) with low nanomolar affinity as determined by isothermal titration calorimetry. In addition, Hoyer et al. used thioflavin T fluorescence to show that the Zab3 dimer completely inhibits Aβ(1-40) fibrillization at stoichiometric concentrations to the Aβ monomer.

    As such, Zab3 represents a novel lead molecule for the development of therapeutics to promote amyloid plaque clearance in vivo according to the peripheral sink mechanism of amyloid dissolution. However, the necessity for a disulfide-linked dimer to bind the peptide may limit its development potential. Although the affibody shows promise in inhibiting fibrils, no data were presented as to whether it can break up fibrils once formed or break up Aβ oligomers which are thought to be the toxic species in the disease.

    Hoyer et al. also used NMR spectroscopy to investigate the molecular basis for Zab3 recognition of Aβ(1-40), and report the high-resolution complex structure of Aβ (1-40) bound to recombinantly expressed Zab3 in solution. The Aβ conformation determined is a β-hairpin where intramolecular backbone hydrogen bonds are observed between two strands across Aβ(17-23 and 30-36).

    This structure represents the first high-resolution structure of the Aβ peptide in a β conformation. The N-terminal region (1-16) of Aβ is disordered in the model. This is consistent with recent structures of antibodies complexed to N-terminal fragments of Aβ (Gardberg et al., 2007; Miles et al., 2008). In our recent structures of Aβ1-16 and 1-28 complexed at the N-terminus to the antibody WO2, the core epitope (2-8) exhibited an extended conformation, while no structure was observed outside of the confines of the antibody binding region (due to flexibility in the residues immediately C-terminal to the epitope).

    Importantly, each face of the Aβ-hairpin structure is largely non-polar, and this conformation of Aβ constitutes the hydrophobic core of the complex structure. The question arises of whether this conformation represents a valid intermediate towards fibrillization as considered by the authors, or is indeed an artifact structure accommodated by the hydrophobic cleft of Zab3.

    Considering the pleomorphic nature of Aβ peptides and the issues highlighted in this forum around the incongruous hydrogen bonding direction observed in this model and in the fibrillar form, at this stage the latter is probable—but not established. However, this does not diminish the importance of this work in providing a molecular template for recognition of the central and C-terminal regions of Aβ, and in providing insights into the inhibition of fibrillization.

    This model is potentially useful in the development of therapeutics designed to clear amyloid plaques via the peripheral sink mechanism. A particularly interesting finding is the similarity of the Zab3 strands that cap the Aβ-hairpin to β-sheet blockers in development as fibrillogenesis inhibitors.

    Finally, it will be fascinating to see whether the affibody approach will lead to molecules that can disrupt preformed Aβ oligomers and protofibrils. It has been observed that metal ions can modulate Aβ toxicity and aggregation in neuronal cultures, with Cu2+ ions increasing Aβ toxicity whilst Zn2+ ions attenuate it (Cuajungco et al., 2005). Thus, drugs such as affibodies that target the oxidative pathway in the disease and reduce the production of toxic Aβ peptides constitute a promising therapeutic approach.

    References:

    . Selection and characterization of Affibody ligands binding to Alzheimer amyloid beta peptides. J Biotechnol. 2007 Jan 30;128(1):162-83. PubMed.

    . Molecular basis for passive immunotherapy of Alzheimer's disease. Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15659-64. PubMed.

    . Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope. J Mol Biol. 2008 Mar 14;377(1):181-92. PubMed.

    . Amyloid-beta metal interaction and metal chelation. Subcell Biochem. 2005;38:235-54. PubMed.

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