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The role of histidines in amyloid β fibril assembly
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
2017 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 591, no 8, p. 1167-1175Article in journal (Refereed) Published
Abstract [en]

Low pH has a strong stabilising effect on the fibrillar assembly of amyloid β, which is associated with Alzheimer's disease. The stabilising effect is already pronounced at pH 6.0, suggesting that protonation of histidines might mediate this effect. Through the systematic substitution of the three native histidines in Aβ for alanines, we have evaluated their role in fibril stability. Using surface plasmon resonance, we show that at neutral pH the fibrillar forms of all His-Ala variants are destabilised by a factor of 4-12 compared to wild-type Aβ. However, none of the His-Ala Aβ variants impair the stabilising effect of the fibril at low pH.

Place, publisher, year, edition, pages
2017. Vol. 591, no 8, p. 1167-1175
Keywords [en]
abeta, amyloid, fibril, histidine, stability, surface plasmon resonance
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-133486DOI: 10.1002/1873-3468.12616ISI: 000400968800009PubMedID: 28267202Scopus ID: 2-s2.0-85017357070OAI: oai:DiVA.org:umu-133486DiVA, id: diva2:1087869
Note

Alternative title: The role of histidines in amyloid beta fibril assembly

Available from: 2017-04-10 Created: 2017-04-10 Last updated: 2023-03-23Bibliographically approved
In thesis
1. Mechanistic and morphological studies of Aβ amyloid formation using surface plasmon resonance
Open this publication in new window or tab >>Mechanistic and morphological studies of Aβ amyloid formation using surface plasmon resonance
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Mekanistiska och morfologiska studier av Aβ amyloidbildning genom yt-plasmon resonans
Abstract [en]

Alzheimer’s disease (AD) is the most common form of dementia and apart from the individual suffering AD also causes a large economic burden for society. AD is associated with progressive neurodegeneration and atrophy of the brain. Extracellular fibrillar assemblies of the amyloid-β peptide (Aβ) in the brain represent a clinical hallmark of AD and these are today considered to be the initial cause of the disease.  The tissue-damaging properties of Aβ assemblies are, however, linked to their structures. Aβ represents a spectrum of peptides between 38-43 residues that can adopt several structures that differ both concerning their morphology and pathological properties. The mechanisms by which Aβ self-assembles, the binding strength of these structures to Aβ monomers, as well as the cross-interaction between different Aβ variants are today not fully understood. Aβ amyloid formation follows a nucleation-dependent mechanism which implies that a kinetically unfavorable nucleus must form before the formation of an amyloid fibril. The elongation of the fibril then proceeds via a template-dependent mechanism where monomeric peptides are incorporated in a highly ordered manner. Using SPR the template-dependent mode of elongation can be selectively monitored. Here, we have used the technique to probe the binding strength of Aβ fibrils and in paper 1 the role of pH and the intrinsic histidines in the Aβ sequence were investigated. The result shows that the histidines do not contribute to the previously observed increase in fibrillar strength at low pH. In paper 2 we analyzed the cross-templation between the in vivo most common variants of Aβ, represented by Aβ1-40 and Aβ1-42. Within this work, we revealed two intrinsic mechanisms preventing Aβ to adopt the structure of the significantly more pathogenic Aβ1-42 variant. In paper 3 we characterized the effect of apolipoprotein E (ApoE) on Aβ amyloid formation. ApoE is today the strongest genetic linker to the development of AD and a well-known binding partner to Aβ fibrils in vivo. Using SPR we can here show that ApoE can prevent Aβ fibril elongation. Although ApoE effectively impairs fibril formation, preventing elongation may result in alternative assemblies with higher cytotoxic properties which hence may explain its pathological effect. In paper 4 we have linked SPR to scanning electron microscopy (SEM). The work presents a novel and generic approach to simultaneously monitor the kinetic properties of amyloid formation, the binding of ligands, and its morphology. We have here specifically probed the binding properties of ApoE to Aβ fibrils, and in combination with immunogold staining technique revealed its binding pattern. Taken together this work pioneers the use of SPR as a powerful technique to elucidate Aβ amyloid formation and the complex enigma of factors causing AD. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2021. p. 57
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2155
National Category
Biochemistry and Molecular Biology Medical and Health Sciences
Research subject
medicinal chemistry; Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-188188 (URN)978-91-7855-658-8 (ISBN)978-91-7855-659-5 (ISBN)
Public defence
Glasburen, KBC, Umeå (English)
Opponent
Supervisors
Available from: 2021-10-08 Created: 2021-10-04 Last updated: 2021-10-05Bibliographically approved

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Brännström, KristofferIslam, TohidulSandblad, LindaOlofsson, Anders

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