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Apolipoprotein E impairs amyloid-β fibril elongation and maturation
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 Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2020 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 287, no 6, p. 1208-1219Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is strongly linked to amyloid depositions of the Aβ peptide (Aβ). The lipid-binding protein apolipoprotein E (ApoE) has been found to interfere with Aβ amyloid formation and to exert a strong clinical impact to the pathology of AD. The APOE gene exists in three allelic isoforms represented by APOE ε2, APOE ε3, and APOE ε4. Carriers of the APOE ε4 variant display a gene dose-dependent increased risk of developing the disease. Aβ amyloids are formed via a nucleation-dependent mechanism where free monomers are added onto a nucleus in a template-dependent manner. Using a combination of surface plasmon resonance and thioflavin-T assays, we here show that ApoE can target the process of fibril elongation and that its interference effectively prevents amyloid maturation. We expose a complex equilibrium where the concentration of ApoE, Aβ monomers, and the amount of already formed Aβ fibrils will affect the relative proportion and formation rate of mature amyloids versus alternative assemblies. The result illustrates a mechanism which may affect both the clearance rate of Aβ assemblies in vivo and the population of cytotoxic Aβ assemblies.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2020. Vol. 287, no 6, p. 1208-1219
Keywords [en]
abeta, amyloid, apolipoprotein E, elongation, surface plasmon resonance
National Category
Basic Medicine Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
biological chemistry
Identifiers
URN: urn:nbn:se:umu:diva-165305DOI: 10.1111/febs.15075ISI: 000519662100010PubMedID: 31571352Scopus ID: 2-s2.0-85075677418OAI: oai:DiVA.org:umu-165305DiVA, id: diva2:1371511
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2023-03-24Bibliographically 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
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Available from: 2021-10-08 Created: 2021-10-04 Last updated: 2021-10-05Bibliographically approved

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Islam, TohidulGharibyan, Anna L.Brännström, KristofferHedberg, IsabellOlofsson, Anders

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