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Islam, T., Gharibyan, A. L., Golchin, S. A., Pettersson, N., Brännström, K., Hedberg, I., . . . Olofsson, A. (2020). Apolipoprotein E impairs amyloid-β fibril elongation and maturation. The FEBS Journal, 287(6), 1208-1219
Open this publication in new window or tab >>Apolipoprotein E impairs amyloid-β fibril elongation and maturation
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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
Keywords
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:nbn:se:umu:diva-165305 (URN)10.1111/febs.15075 (DOI)000519662100010 ()31571352 (PubMedID)
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2020-04-02Bibliographically approved
Gharibyan, A., Islam, T., Pettersson, N., Golchin, S. A., Lundgren, J., Johansson, G., . . . Olofsson, A. (2020). Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity. Biomolecules, 10(1), Article ID 134.
Open this publication in new window or tab >>Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity
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2020 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 10, no 1, article id 134Article in journal (Refereed) Published
Abstract [en]

Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
apolipoprotein E, IAPP amyloid, Thioflavin T, pericytes, cytotoxicity
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-168881 (URN)10.3390/biom10010134 (DOI)000514863200033 ()31947546 (PubMedID)
Funder
The Swedish Brain Foundation, FO2018-0334Swedish Research Council, 199-0469Stiftelsen Gamla Tjänarinnor, 2018-00718
Available from: 2020-03-19 Created: 2020-03-19 Last updated: 2020-03-19Bibliographically approved
Islam, T., Gharibyan, A. L., Lee, C. C. & Olofsson, A. (2019). Morphological analysis of Apolipoprotein E binding to A beta Amyloid using a combination of Surface Plasmon Resonance, Immunogold Labeling and Scanning Electron Microscopy. BMC Biotechnology, 19(1), Article ID 97.
Open this publication in new window or tab >>Morphological analysis of Apolipoprotein E binding to A beta Amyloid using a combination of Surface Plasmon Resonance, Immunogold Labeling and Scanning Electron Microscopy
2019 (English)In: BMC Biotechnology, ISSN 1472-6750, E-ISSN 1472-6750, Vol. 19, no 1, article id 97Article in journal (Refereed) Published
Abstract [en]

Background: Immunogold labeling in combination with transmission electron microscopy analysis is a technique frequently used to correlate high-resolution morphology studies with detailed information regarding localization of specific antigens. Although powerful, the methodology has limitations and it is frequently difficult to acquire a stringent system where unspecific low-affinity interactions are removed prior to analysis.

Results: We here describe a combinatorial strategy where surface plasmon resonance and immunogold labeling are used followed by a direct analysis of the sensor-chip surface by scanning electron microscopy. Using this approach, we have probed the interaction between amyloid-beta fibrils, associated to Alzheimer's disease, and apolipoprotein E, a well-known ligand frequently found co-deposited to the fibrillar form of A beta in vivo. The results display a lateral binding of ApoE along the amyloid fibrils and illustrates how the gold-beads represent a good reporter of the binding.

Conclusions: This approach exposes a technique with generic features which enables both a quantitative and a morphological evaluation of a ligand-receptor based system. The methodology mediates an advantage compared to traditional immunogold labeling since all washing steps can be monitored and where a high stringency can be maintained throughout the experiment.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
A beta, ApoE, Immunogold, Surface plasmon resonance, SPR, Scanning electron microscopy, SEM, Fibrils, Morphology, Abeta
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:umu:diva-168577 (URN)10.1186/s12896-019-0589-4 (DOI)000513564300001 ()31829176 (PubMedID)
Funder
The Dementia Association - The National Association for the Rights of the DementedThe Swedish Brain Foundation
Available from: 2020-03-03 Created: 2020-03-03 Last updated: 2020-03-06Bibliographically approved
Singh, P., Adolfsson, D. E., Ådén, J., Cairns, A. G., Bartens, C., Brännström, K., . . . Almqvist, F. (2019). Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding. Journal of Organic Chemistry, 84(7), 3887-3903
Open this publication in new window or tab >>Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding
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2019 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 7, p. 3887-3903Article in journal (Refereed) Published
Abstract [en]

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-157464 (URN)10.1021/acs.joc.8b03015 (DOI)000464250800014 ()30862161 (PubMedID)
Funder
Swedish Research Council, 2014-04673Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031The Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2019-06-13Bibliographically approved
Zhang, J., Grundström, C., Brännström, K., Iakovleva, I., Lindberg, M. J., Olofsson, A., . . . Sauer-Eriksson, A. E. (2018). Interspecies variation between fish and human transthyretins in their binding of thyroid-disrupting chemicals. Environmental Science and Technology, 52(20), 11865-11874
Open this publication in new window or tab >>Interspecies variation between fish and human transthyretins in their binding of thyroid-disrupting chemicals
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2018 (English)In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 52, no 20, p. 11865-11874Article in journal (Refereed) Published
Abstract [en]

Thyroid-disrupting chemicals (TDCs) are xenobiotics that can interfere with the endocrine system and cause adverse effects in organisms and their offspring. TDCs affect both the thyroid gland and regulatory enzymes associated with thyroid hormone homeostasis. Transthyretin (TTR) is found in the serum and cerebrospinal fluid of vertebrates, where it transports thyroid hormones. Here, we explored the interspecies variation in TDC binding to human and fish TTR (exemplified by Gilthead seabream (Sparus aurata)). The in vitro binding experiments showed that TDCs bind with equal or weaker affinity to seabream TTR than to the human TTR, in particular, the polar TDCs (>500-fold lower affinity). Crystal structures of the seabream TTR TDC complexes revealed that all TDCs bound at the thyroid binding sites. However, amino acid substitution of Ser117 in human TTR to Thr117 in seabream prevented polar TDCs from binding deep in the hormone binding cavity, which explains their low affinity to seabream TTR Molecular dynamics and in silico alanine scanning simulation also suggested that the protein backbone of seabream TTR is more rigid than the human one and that Thr117 provides fewer electrostatic contributions than Ser117 to ligand binding. This provides an explanation for the weaker affinities of the ligands that rely on electrostatic interactions with Thr117. The lower affinities of TDCs to fish TTR, in particular the polar ones, could potentially lead to milder thyroid-related effects in fish.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-153704 (URN)10.1021/acs.est.8b03581 (DOI)000447816100046 ()30226982 (PubMedID)
Funder
Swedish Research Council Formas, 210-2012-131Swedish Research Council, 521-2011-6427Swedish Research Council, 2015-03607
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-05Bibliographically approved
Brännström, K., Gharibyan, A. L., Islam, T., Iakovleva, I., Nilsson, L., Lee, C. C., . . . Olofsson, A. (2018). Scanning electron microscopy as a tool for evaluating morphology of amyloid structures formed on surface plasmon resonance chips. Data in Brief, 19, 1166-1170
Open this publication in new window or tab >>Scanning electron microscopy as a tool for evaluating morphology of amyloid structures formed on surface plasmon resonance chips
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2018 (English)In: Data in Brief, E-ISSN 2352-3409, Vol. 19, p. 1166-1170Article in journal (Refereed) Published
Abstract [en]

We demonstrate the use of Scanning Electron microscopy (SEM) in combination with Surface Plasmon Resonance (SPR) to probe and verify the formation of amyloid and its morphology on an SPR chip. SPR is a technique that measures changes in the immobilized weight on the chip surface and is frequently used to probe the formation and biophysical properties of amyloid structures. In this context it is of interest to also monitor the morphology of the formed structures. The SPR chip surface is made of a layer of gold, which represent a suitable material for direct analysis of the surface using SEM. The standard SPR chip used here (CM5-chip, GE Healthcare, Uppsala, Sweden) can easily be disassembled and directly analyzed by SEM. In order to verify the formation of amyloid fibrils in our experimental conditions we analyzed also in-solution produced structures by using Transmission Electron Microscopy (TEM). For further details and experimental findings, please refer to the article published in Journal of Molecular Biology, (Brännström K. et al., 2018) [1].

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-149049 (URN)10.1016/j.dib.2018.05.129 (DOI)000449869100149 ()30228999 (PubMedID)2-s2.0-85047834173 (Scopus ID)
Note

Refers to: Kristoffer Brännström, Tohidul Islam, Anna L. Gharibyan, Irina Iakovleva, Lina Nilsson, Cheng Choo Lee, Linda Sandblad, Annelie Pamrén, Anders Olofsson. The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation. Journal of Molecular Biology, Volume 430, Issue 13, 22 June 2018, Pages 1940-1949

Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2019-02-04Bibliographically approved
Brännström, K., Islam, T., Gharibyan, A. L., Iakovleva, I., Nilsson, L., Lee, C. C., . . . Olofsson, A. (2018). The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation. Journal of Molecular Biology, 430(13), 1940-1949
Open this publication in new window or tab >>The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation
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2018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 13, p. 1940-1949Article in journal (Refereed) Published
Abstract [en]

Fibril formation of the amyloid-β peptide (Aβ) follows a nucleation-dependent polymerization process and is associated with Alzheimer's disease. Several different lengths of Aβ are observed in vivo, but Aβ1-40 and Aβ1-42 are the dominant forms. The fibril architectures of Aβ1-40 and Aβ1-42 differ and Aβ1-42 assemblies are generally considered more pathogenic. We show here that monomeric Aβ1-42 can be cross-templated and incorporated into the ends of Aβ1-40 fibrils, while incorporation of Aβ1-40 monomers into Aβ1-42 fibrils is very poor. We also show that via cross-templating incorporated Aβ monomers acquire the properties of the parental fibrils. The suppressed ability of Aβ1-40 to incorporate into the ends of Aβ1-42 fibrils and the capacity of Aβ1-42 monomers to adopt the properties of Aβ1-40 fibrils may thus represent two mechanisms reducing the total load of fibrils having the intrinsic, and possibly pathogenic, features of Aβ1-42 fibrils in vivo. We also show that the transfer of fibrillar properties is restricted to fibril-end templating and does not apply to cross-nucleation via the recently described path of surface-catalyzed secondary nucleation, which instead generates similar structures to those acquired via de novo primary nucleation in the absence of catalyzing seeds. Taken together these results uncover an intrinsic barrier that prevents Aβ1-40 from adopting the fibrillar properties of Aβ1-42 and exposes that the transfer of properties between amyloid-β fibrils are determined by their path of formation.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Aβ, Cross-templating, Fibril, Surface Plasmon resonance, Thioflavin-T
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-148050 (URN)10.1016/j.jmb.2018.05.001 (DOI)29751013 (PubMedID)2-s2.0-85047103029 (Scopus ID)
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-06-14Bibliographically approved
Bugaytsova, J. A., Björnham, O., Chernov, Y. A., Gideonsson, P., Henriksson, S., Mendez, M., . . . Boren, T. (2017). Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence. Cell Host and Microbe, 21(3), 376-389
Open this publication in new window or tab >>Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence
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2017 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389Article in journal (Refereed) Published
Abstract [en]

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-132788 (URN)10.1016/j.chom.2017.02.013 (DOI)000396375600023 ()28279347 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2020-04-08Bibliographically approved
Brännström, K., Islam, T., Sandblad, L. & Olofsson, A. (2017). The role of histidines in amyloid β fibril assembly. FEBS Letters, 591(8), 1167-1175
Open this publication in new window or tab >>The role of histidines in amyloid β fibril assembly
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.

Keywords
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:nbn:se:umu:diva-133486 (URN)10.1002/1873-3468.12616 (DOI)000400968800009 ()28267202 (PubMedID)
Note

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

Available from: 2017-04-10 Created: 2017-04-10 Last updated: 2018-06-09Bibliographically approved
Nilsson, L., Larsson, A., Begum, A., Iakovleva, I., Carlsson, M., Kristoffer, B., . . . Olofsson, A. (2016). Modifications of the 7-Hydroxyl Group of the Transthyretin Ligand Luteolin Provide Mechanistic Insights into Its Binding Properties and High Plasma Specificity. PLoS ONE, 11(4), Article ID e0153112.
Open this publication in new window or tab >>Modifications of the 7-Hydroxyl Group of the Transthyretin Ligand Luteolin Provide Mechanistic Insights into Its Binding Properties and High Plasma Specificity
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153112Article in journal (Refereed) Published
Abstract [en]

Amyloid formation of the plasma protein transthyretin (TTR) has been linked to familial amyloid polyneuropathy and senile systemic amyloidosis. Binding of ligands within its natural hormone binding site can stabilize the tetrameric structure and impair amyloid formation. We have recently shown that the flavonoid luteolin stabilizes TTR in human plasma with a very high selectivity. Luteolin, however, is inactivated in vivo via glucuronidation for which the preferred site is the hydroxy group at position 7 on its aromatic A-ring. We have evaluated the properties of two luteolin variants in which the 7-hydroxy group has been exchanged for a chlorine (7-Cl-Lut) or a methoxy group (7-MeO-Lut). Using an in vitro model, based on human liver microsomes, we verified that these modifications increase the persistence of the drug. Crystal structure determinations show that 7-Cl-Lut binds similarly to luteolin. The larger MeO substituent cannot be accommodated within the same space as the chlorine or hydroxy group and as a result 7-MeO-Lut binds in the opposite direction with the methoxy group in position 7 facing the solvent. Both 7-Cl-Lut and 7-MeO-Lut qualify as high-affinity binders, but in contrast to luteolin, they display a highly non-specific binding to other plasma components. The binding of the two conformations and the key-interactions to TTR are discussed in detail. Taken together, these results show a proof-of-concept that the persistence of luteolin towards enzymatic modification can be increased. We reveal two alternative high-affinity binding modes of luteolin to TTR and that modification in position 7 is restricted only to small substituents if the original orientation of luteolin should be preserved. In addition, the present work provides a general and convenient method to evaluate the efficacy of TTR-stabilizing drugs under conditions similar to an in vivo environment.

Place, publisher, year, edition, pages
Public Library Science, 2016
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-119997 (URN)10.1371/journal.pone.0153112 (DOI)000373603500101 ()27050398 (PubMedID)
Available from: 2016-05-04 Created: 2016-05-04 Last updated: 2018-06-07Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-8743-8720

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