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Design of oligomer-specific antibodies
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
URN: urn:nbn:se:umu:diva-54051OAI: oai:DiVA.org:umu-54051DiVA, id: diva2:515383
Tillgänglig från: 2012-04-12 Skapad: 2012-04-12 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Targeting cytotoxic species in amyloid diseases
Öppna denna publikation i ny flik eller fönster >>Targeting cytotoxic species in amyloid diseases
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Amyloid diseases are a world-wide problem causing great human suffer and large economical costs. Although amyloid deposits, a common denominator in all amyloid disorders, are detrimental to the surrounding tissue, there is a poor correlation between total amyloid burden and clinical symptoms. Soluble oligomers are much more potent to exert a tissue damaging effect. 

Alzheimer’s disease (AD) is strongly linked to self-assembly of the amyloid-β (Aβ) peptide. Antibodies selectively targeting cytotoxic Aβ-species are useful both for understanding oligomer formation and for their therapeutic abilities. We hypothesized that the effect of avidity would compensate for a low single site affinity and be enough to selectively target oligomers. To evaluate this hypothesis, we focused on the IgM isotype having ten antigen-binding sites. In accordance with the hypothesis, the IgM isotype effectively bound oligomeric Aβ also in presence of a vast excess of its monomeric counterpart, clearly illustrating the potentiating effect of avidity. As a continuation of this work, we have shown that the avidity effect from a bivalent binding is enough to induce oligomer specificity. This finding facilitates a direct application on the clinically more useful IgG isotype, where the binding properties now can be controlled in detail. The method is general and we have, using this technique, also designed oligomer specific antibodies targeting α-synuclein.

Transthyretin (TTR) is an amyloidogenic protein involved in both hereditary and sporadic amyloidosis. The cytotoxicity of TTR is intriguing since studies have shown cytotoxic potential from oligomers, tetramers and even monomers. Elucidation of the molecular properties associated with TTR cytotoxicity is hence of interest. By preventing tetramer dissociation, TTR aggregation and TTR-induced cytotoxicity is abolished. Based on this rationale, a current therapeutic strategy is to stabilize the TTR tetramer with small molecules. The kinetic stability within the spectra of known TTR mutations spans more than three orders of magnitude. However, although the most stable mutants are inert, a poor correlation within the group of cytotoxic variants exists where the cytotoxic effect is not potentiated in proportion to their kinetic stability. Through analysis of a large spectra of TTR variants, our results indicate that TTR induced cytotoxicity requires an intermediate stability of the TTR molecule. The kinetic stability should be low enough to permit tetramer dissociation and the thermodynamic stability high enough to prevent instant aggregation and to allow formation of the cytotoxic fold. 

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2012. s. 63
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1494
Nyckelord
Alzheimer's disease, Amyloid-beta, transthyretin, FAP, amyloid, cytotoxic species, oligomers
Nationell ämneskategori
Cell- och molekylärbiologi Annan medicinsk grundvetenskap
Forskningsämne
medicinsk biokemi
Identifikatorer
urn:nbn:se:umu:diva-54006 (URN)978-91-7459-414-0 (ISBN)
Disputation
2012-05-04, KB3A9, KBC, Umeå universitet, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2012-04-12 Skapad: 2012-04-11 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Brännström, KristofferLindhagen Persson, MalinBrännström, ThomasMorozova-Roche, LudmillaOlofsson, Anders

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Brännström, KristofferLindhagen Persson, MalinBrännström, ThomasMorozova-Roche, LudmillaOlofsson, Anders
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Institutionen för medicinsk kemi och biofysikPatologi
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

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