Dataset Information

Molecular Recognition between A?-Specific Single-Domain Antibody and A? Misfolded Aggregates.

ABSTRACT: A? is the toxic amyloid polypeptide responsible for Alzheimer's disease (AD). Prevention and elimination of the A? misfolded aggregates are the promising therapeutic strategies for the AD treatments. Gammabody, the A?-Specific Single-domain (VH) antibody, recognizes A? aggregates with high affinity and specificity and reduces their toxicities. Employing the molecular dynamics simulations, we studied diverse gammabody-A? recognition complexes to get insights into their structural and dynamic properties and gammabody-A? recognitions. Among many heterogeneous binding modes, we focused on two gammabody-A? recognition scenarios: recognition through A? ?-sheet backbone and on sidechain surface. We found that the gammabody primarily uses the complementarity-determining region 3 (CDR3) loop with the grafted A? sequence to interact with the A? fibril, while CDR1/CDR2 loops have very little contact. The gammabody-A? complexes with backbone binding mode are more stable, explaining the gammabody's specificity towards the C-terminal A? sequence.

SUBMITTER: Zhang M

PROVIDER: S-EPMC6640678 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Molecular Recognition between Aβ-Specific Single-Domain Antibody and Aβ Misfolded Aggregates.

Zhang Mingzhen M Zheng Jie J Nussinov Ruth R Ma Buyong B

Antibodies (Basel, Switzerland) 20180713 3

Aβ is the toxic amyloid polypeptide responsible for Alzheimer's disease (AD). Prevention and elimination of the Aβ misfolded aggregates are the promising therapeutic strategies for the AD treatments. Gammabody, the Aβ-Specific Single-domain (VH) antibody, recognizes Aβ aggregates with high affinity and specificity and reduces their toxicities. Employing the molecular dynamics simulations, we studied diverse gammabody-Aβ recognition complexes to get insights into their structural and dynamic prop ...[more]

PMID: 31544877

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Project description:BackgroundThe form(s) of amyloid-β peptide (Aβ) associated with the pathology characteristic of Alzheimer's disease (AD) remains unclear. In particular, the neurotoxicity of intraneuronal Aβ accumulation is an issue of considerable controversy; even the existence of Aβ deposits within neurons has recently been challenged by Winton and co-workers. These authors purport that it is actually intraneuronal APP that is being detected by antibodies thought to be specific for Aβ. To further address this issue, an anti-Aβ antibody was developed (MOAB-2) that specifically detects Aβ, but not APP. This antibody allows for the further evaluation of the early accumulation of intraneuronal Aβ in transgenic mice with increased levels of human Aβ in 5xFAD and 3xTg mice.ResultsMOAB-2 (mouse IgG2b) is a pan-specific, high-titer antibody to Aβ residues 1-4 as demonstrated by biochemical and immunohistochemical analyses (IHC), particularly compared to 6E10 (a commonly used commercial antibody to Aβ residues 3-8). MOAB-2 did not detect APP or APP-CTFs in cell culture media/lysates (HEK-APPSwe or HEK-APPSwe/BACE1) or in brain homogenates from transgenic mice expressing 5 familial AD (FAD) mutation (5xFAD mice). Using IHC on 5xFAD brain tissue, MOAB-2 immunoreactivity co-localized with C-terminal antibodies specific for Aβ40 and Aβ42. MOAB-2 did not co-localize with either N- or C-terminal antibodies to APP. In addition, no MOAB-2-immunoreactivity was observed in the brains of 5xFAD/BACE-/- mice, although significant amounts of APP were detected by N- and C-terminal antibodies to APP, as well as by 6E10. In both 5xFAD and 3xTg mouse brain tissue, MOAB-2 co-localized with cathepsin-D, a marker for acidic organelles, further evidence for intraneuronal Aβ, distinct from Aβ associated with the cell membrane. MOAB-2 demonstrated strong intraneuronal and extra-cellular immunoreactivity in 5xFAD and 3xTg mouse brain tissues.ConclusionsBoth intraneuronal Aβ accumulation and extracellular Aβ deposition was demonstrated in 5xFAD mice and 3xTg mice with MOAB-2, an antibody that will help differentiate intracellular Aβ from APP. However, further investigation is required to determine whether a molecular mechanism links the presence of intraneuronal Aβ with neurotoxicity. As well, understanding the relevance of these observations to human AD patients is critical.

Dataset Information

Molecular Recognition between A?-Specific Single-Domain Antibody and A? Misfolded Aggregates.

Publications

Molecular Recognition between Aβ-Specific Single-Domain Antibody and Aβ Misfolded Aggregates.

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