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Structural and functional analyses of pyroglutamate-amyloid-?-specific antibodies as a basis for Alzheimer immunotherapy.

ABSTRACT: Alzheimer disease is associated with deposition of the amyloidogenic peptide A? in the brain. Passive immunization using A?-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo Because N-terminally truncated pyroglutamate (pE)-modified A? species (A?pE3) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separate monoclonal antibodies that specifically recognize A?pE3 with affinities of 1-10 nm and inhibit A?pE3 fibril formation in vitro. In vivo application of one of these resulted in improved memory in A?pE3 oligomer-treated mice. Crystal structures of Fab-A?pE3 complexes revealed two distinct binding modes for the peptide. Juxtaposition of pyroglutamate pE3 and the F4 side chain (the "pEF head") confers a pronounced bulky hydrophobic nature to the A?pE3 N terminus that might explain the enhanced aggregation properties of the modified peptide. The deep burial of the pEF head by two of the antibodies explains their high target specificity and low cross-reactivity, making them promising candidates for the development of clinical antibodies.

SUBMITTER: Piechotta A

PROVIDER: S-EPMC5535044 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Structural and functional analyses of pyroglutamate-amyloid-β-specific antibodies as a basis for Alzheimer immunotherapy.

Piechotta Anke A Parthier Christoph C Kleinschmidt Martin M Gnoth Kathrin K Pillot Thierry T Lues Inge I Demuth Hans-Ulrich HU Schilling Stephan S Rahfeld Jens-Ulrich JU Stubbs Milton T MT

The Journal of biological chemistry 20170616 30

Alzheimer disease is associated with deposition of the amyloidogenic peptide Aβ in the brain. Passive immunization using Aβ-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo Because N-terminally truncated pyroglutamate (pE)-modified Aβ species (AβpE3) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separa ...[more]

PMID: 28623233

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Project description:A series of human autoantibodies against thyroglobulin (Tg) which exhibit different specificities for iodothyronines were studied. The ability of a thyroxine (T4)-containing peptide (T4P) isolated from human thyroglobulin (Tg) to displace [125I]T3 from human T3-specific autoantisera was 11-50 times greater than that of T4 alone. These antisera therefore strongly recognize amino acids adjacent to T4 in the Tg structure. This was confirmed when a Tg preparation (Tg[0.05]) containing an average of only 0.05 of a T4 residue/molecule and much less T3 had good cross-reactivities with these antisera. Cross-reactivities of other Tg preparations with different T4 contents increased only slowly with increase of T4 content up to a mean of 6.6 residues/molecule and were not proportional to T3 content. In contrast, cross-reactivities with a human T4-specific autoantiserum were strongly dependent on T4 content. Tg[0.05] was 500 times less reactive than T4P and 615 times less than T4. Cross-reactivities rose rapidly as the T4 content of Tg preparations increased from a mean of 0.05 to approx. 1-2 residues/molecule. Thyroxine is therefore a dominant feature of the antigenic site for this antiserum. There was little further increase in cross-reactivities for those Tg preparations containing up to an average of 6.6 residues T4 per molecule, confirming previous conclusions that all T4-containing sites are not immunologically identical and that autoantibodies exhibit a preference for particular sites on Tg. Similar conclusions were reached for a non-specific iodothyronine-binding antiserum. These results indicate that iodothyronine specificity in human autoantisera is not necessarily determined by the iodothyronine present in the immunogenic area, but by the precise site selected by the immune response. T4- or non-specific antibodies have thyroxine as a dominant feature of the antigenic site. T3- specific antibodies have the thyroxine residue as a peripheral feature of the binding site, and it is not necessary to postulate that T3 was part of the immunogen or is required in the epitope. These antisera may have value in mapping the hormonogenic regions in Tg from human and other species.

Dataset Information

Structural and functional analyses of pyroglutamate-amyloid-?-specific antibodies as a basis for Alzheimer immunotherapy.

Publications

Structural and functional analyses of pyroglutamate-amyloid-β-specific antibodies as a basis for Alzheimer immunotherapy.

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