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Abelein, Axel
Publications (10 of 11) Show all publications
Wallin, C., Kulkarni, Y. S., Abelein, A., Jarvet, J., Liao, Q., Strodel, B., . . . Wärmländer, S. K. T. (2016). Characterization of Mn(II) ion binding to the amyloid-beta peptide in Alzheimer's disease. Journal of Trace Elements in Medicine and Biology, 38, 183-193
Open this publication in new window or tab >>Characterization of Mn(II) ion binding to the amyloid-beta peptide in Alzheimer's disease
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2016 (English)In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 38, p. 183-193Article in journal (Refereed) Published
Abstract [en]

Growing evidence links neurodegenerative diseases to metal exposure. Aberrant metal ion concentrations have been noted in Alzheimer's disease (AD) brains, yet the role of metals in AD pathogenesis remains unresolved. A major factor in AD pathogenesis is considered to be aggregation of and amyloid formation by amyloid-beta (A beta) peptides. Previous studies have shown that A beta displays specific binding to Cu(II) and Zn(II) ions, and such binding has been shown to modulate A beta aggregation. Here, we use nuclear magnetic resonance (NMR) spectroscopy to show that Mn(II) ions also bind to the N-terminal part of the A beta(1-40) peptide, with a weak binding affinity in the milli- to micromolar range. Circular dichroism (CD) spectroscopy, solid state atomic force microscopy (AFM), fluorescence spectroscopy, and molecular modeling suggest that the weak binding of Mn(II) to A beta may not have a large effect on the peptide's aggregation into amyloid fibrils. However, identification of an additional metal ion displaying A beta binding reveals more complex AD metal chemistry than has been previously considered in the literature.

Keywords
Manganese, Neurodegeneration, Metal-protein binding, Spectroscopy, Molecular dynamics
National Category
Biological Sciences Immunology in the medical area
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-136238 (URN)10.1016/j.jtemb.2016.03.009 (DOI)000385473600023 ()27085215 (PubMedID)
Available from: 2016-12-12 Created: 2016-12-01 Last updated: 2022-02-28Bibliographically approved
Abelein, A., Jarvet, J., Barth, A., Gräslund, A. & Danielsson, J. (2016). Ionic Strength Modulation of the Free Energy Landscape of A beta(40) Peptide Fibril Formation. Journal of the American Chemical Society, 138(21), 6893-6902
Open this publication in new window or tab >>Ionic Strength Modulation of the Free Energy Landscape of A beta(40) Peptide Fibril Formation
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2016 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 21, p. 6893-6902Article in journal (Refereed) Published
Abstract [en]

Protein misfolding and formation of cross-beta structured amyloid fibrils are linked to, many neurodegenerative disorders. Although recently developed,quantitative approaches have started to reveal the molecular nature of self-assembly and fibril formation of proteins and peptides, it is yet unclear how these self-organization events are precisely modulated by microenvironmental factors, which are known to strongly affect the macroscopic aggregation properties. Here, we characterize the explicit effect of ionic strength on the microscopic aggregation rates of amyloid beta peptide (A beta 40) self-association, implicated in Alzheimer's disease. We found that physiological ionic strength accelerates A beta 40 aggregation kinetics by promoting surface-catalyzed secondary nucleation reactions. This promoted catalytic effect can be assigned to shielding of electrostatic repulsion between Monomers on the fibril surface or between the fibril surface itself and monomeric peptides. Furthermore, we observe the formation of two different beta-structured states with =similar but distinct spectroscopic features, which can be assigned to an off-pathway immature state (F-beta*) and a mature stable State (F-beta), where salt favors formation of the F-beta fibril morphology. Addition of salt to preformed F-beta* accelerates transition to F-beta, underlining the dynamic nature of A beta 40 fibrils in solution. On the basis of,these results we suggest a model where salt decreases the free-energy barrier for A beta 40 folding to the F-beta state, favoring the buildup of the mature fibril morphology while omitting competing, energetically less favorable structural states.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-131935 (URN)10.1021/jacs.6b04511 (DOI)000377151400029 ()27171340 (PubMedID)
Available from: 2016-07-05 Created: 2016-07-04 Last updated: 2022-02-23Bibliographically approved
Abelein, A. (2015). Modulation of Alzheimer's amyloid β peptide self-assembly: Insights into molecular mechanisms of peptide aggregation associated with Alzheimer's disease. (Doctoral dissertation). Stockholm: Department of Biochemistry and Biophysics, Stockholm University
Open this publication in new window or tab >>Modulation of Alzheimer's amyloid β peptide self-assembly: Insights into molecular mechanisms of peptide aggregation associated with Alzheimer's disease
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Misfolding of proteins and peptides is closely linked to several neurodegenerative disorders, among them Alzheimer's disease (AD), the most prominent example of brain diseases. The self-assembly of the amyloid β peptide (Aβ) into amyloid fibrils is one histologic hallmark of AD. A detailed knowledge about the underlying mechanism(s) of Aβ aggregation is crucial for advances toward a fundamental understanding of the disease, which may promote the search for and design of efficient therapeutics. The work presented in this thesis deals with modulation of the aggregation process by various compounds, i.e. small organic molecules (e.g. lacmoid and Congo red), surfactants and metal ions. These results provide insight into the molecular mechanism of modulator interactions and interference with Aβ and its aggregation pathways. Applying a combination of kinetic and dynamic studies as well as structural investigations we characterized the molecular interactions between Aβ and aggregation modulators in terms of microscopic rate constants, conformational preferences and thermodynamics. An important conclusion is that these modulators form highly dynamic complexes with Aβ, with life-times on the timescale of milliseconds. Despite the similar exchange dynamics, the effect on peptide aggregation is modulator-specific and fibril formation can be accelerated, retarded or inhibited by their interactions. In summary, Aβ self-assembly is governed by microscopic kinetic and dynamic processes that can be altered by aggregation modulators. Further elucidation of these mechanisms is beneficial for the understanding and therapeutic intervention of amyloid diseases.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2015. p. 49
National Category
Biophysics
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-114172 (URN)978-91-7649-104-1 (ISBN)
Public defence
2015-03-27, Magnéli hall, Arrhenius Laboratory, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2015-03-05 Created: 2015-02-23 Last updated: 2022-02-23Bibliographically approved
Abelein, A., Gräslund, A. & Danielsson, J. (2015). Zinc as chaperone-mimicking agent for retardation of amyloid beta peptide fibril formation. Proceedings of the National Academy of Sciences of the United States of America, 112(17), 5407-5412
Open this publication in new window or tab >>Zinc as chaperone-mimicking agent for retardation of amyloid beta peptide fibril formation
2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 17, p. 5407-5412Article in journal (Refereed) Published
Abstract [en]

Metal ions have emerged to play a key role in the aggregation process of amyloid beta (A beta) peptide that is closely related to the pathogenesis of Alzheimer's disease. A detailed understanding of the underlying mechanistic process of peptide-metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic A beta-Zn2+ binding features as well as how Zn2+ modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn2+ effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc A beta(40) aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn2+, the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn2+ transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn2+ ion, forming a marginally stable, short-lived folded A beta(40) species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded A beta(40)-Zn2+ complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for A beta(40).

Keywords
Alzheimer's disease, amyloid beta peptide, aggregation kinetics, zinc ion interactions, NMR relaxation
National Category
Biological Sciences Basic Medicine
Identifiers
urn:nbn:se:su:diva-117444 (URN)10.1073/pnas.1421961112 (DOI)000353554000052 ()25825723 (PubMedID)
Note

AuthorCount:3;

Available from: 2015-05-21 Created: 2015-05-19 Last updated: 2022-02-23Bibliographically approved
Abelein, A., Abrahams, J. P., Danielsson, J., Gräslund, A., Jarvet, J., Luo, J., . . . Wärmländer, S. K. T. (2014). The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway. Journal of Biological Inorganic Chemistry, 19(4-5), 623-634
Open this publication in new window or tab >>The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway
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2014 (English)In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, no 4-5, p. 623-634Article, review/survey (Refereed) Published
Abstract [en]

The amyloid beta (A beta) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the A beta peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the A beta peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of A beta complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.

Keywords
Alzheimer's disease, Amyloid beta peptide, Hairpin, Protein aggregation, Neurotoxicity
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-105411 (URN)10.1007/s00775-014-1131-8 (DOI)000336310000013 ()
Note

AuthorCount:8;

Available from: 2014-06-25 Created: 2014-06-24 Last updated: 2022-02-23Bibliographically approved
Abelein, A., Lang, L., Lendel, C., Gräslund, A. & Danielsson, J. (2013). Corrigendum to “Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly” [FEBS Lett. 586 (2012) 3991–3995]. FEBS Letters, 587(9), 1452-1452
Open this publication in new window or tab >>Corrigendum to “Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly” [FEBS Lett. 586 (2012) 3991–3995]
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2013 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, no 9, p. 1452-1452Article in journal, Editorial material (Other academic) Published
National Category
Biophysics
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-114170 (URN)10.1016/j.febslet.2013.03.009 (DOI)000317750100031 ()
Available from: 2015-02-23 Created: 2015-02-23 Last updated: 2022-02-23Bibliographically approved
Abelein, A., Kaspersen, J. D., Nielsen, S. B., Jensen, G. V., Christiansen, G., Pedersen, J. S., . . . Gräslund, A. (2013). Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates. Journal of Biological Chemistry, 288(32), 23518-23528
Open this publication in new window or tab >>Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates
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2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 32, p. 23518-23528Article in journal (Refereed) Published
Abstract [en]

Intermediate amyloidogenic states along the amyloid β peptide (Aβ) aggregation pathway have been shown to be linked to neurotoxicity. To shed more light on the different structures that may arise during Aβ aggregation, we here investigate surfactant-induced Aβ aggregation. This process leads to co-aggregates featuring a β-structure motif that is characteristic for mature amyloid-like structures. Surfactants induce secondary structure in Aβ in a concentration-dependent manner, from predominantly random coil at low surfactant concentration, via β-structure to the fully formed α-helical state at high surfactant concentration. The β-rich state is the most aggregation-prone as monitored by thioflavin T fluorescence. Small angle x-ray scattering reveals initial globular structures of surfactant-Aβ co-aggregated oligomers and formation of elongated fibrils during a slow aggregation process. Alongside this slow (minutes to hours time scale) fibrillation process, much faster dynamic exchange (k(ex) ∼1100 s(-1)) takes place between free and co-aggregate-bound peptide. The two hydrophobic segments of the peptide are directly involved in the chemical exchange and interact with the hydrophobic part of the co-aggregates. Our findings suggest a model for surfactant-induced aggregation where free peptide and surfactant initially co-aggregate to dynamic globular oligomers and eventually form elongated fibrils. When interacting with β-structure promoting substances, such as surfactants, Aβ is kinetically driven toward an aggregation-prone state.

National Category
Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-98634 (URN)10.1074/jbc.M113.470450 (DOI)000330598200056 ()23775077 (PubMedID)
Available from: 2014-01-08 Created: 2014-01-08 Last updated: 2022-03-23Bibliographically approved
Abelein, A. (2013). Modulation of amyloid β peptide self-assembly: Aggregation mechanisms associated with Alzheimer's disease. (Licentiate dissertation). Stockholm: Department of Biochemistry and Biophysics, Stockholm University
Open this publication in new window or tab >>Modulation of amyloid β peptide self-assembly: Aggregation mechanisms associated with Alzheimer's disease
2013 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2013. p. 22
National Category
Biophysics
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-89078 (URN)
Presentation
2013-04-09, Magnéli hall, 14:30 (English)
Opponent
Supervisors
Available from: 2013-04-10 Created: 2013-04-10 Last updated: 2022-02-24Bibliographically approved
Abelein, A., Bolognesi, B., Dobson, C. M., Gräslund, A. & Lendel, C. (2012). Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid β self-assembly. Biochemistry, 51(1), 126-137
Open this publication in new window or tab >>Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid β self-assembly
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2012 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 51, no 1, p. 126-137Article in journal (Refereed) Published
Abstract [en]

The link between many neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, and the aberrant folding and aggregation of proteins has prompted a comprehensive search for small organic molecules that have the potential to inhibit such processes. Although many compounds have been reported to affect the formation of amyloid fibrils and/or other types of protein aggregates, the mechanisms by which they act are not well understood. A large number of compounds appear to act in a nonspecific way affecting several different amyloidogenic proteins. We describe here a detailed study of the mechanism of action of one representative compound, lacmoid, in the context of the inhibition of the aggregation of the amyloid β-peptide (Aβ) associated with Alzheimer's disease. We show that lacmoid binds Aβ(1-40) in a surfactant-like manner and counteracts the formation of all types of Aβ(1-40) and Aβ(1-42) aggregates. On the basis of these and previous findings, we are able to rationalize the molecular mechanisms of action of nonspecific modulators of protein self-assembly in terms of hydrophobic attraction and the conformational preferences of the polypeptide.

National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-85269 (URN)10.1021/bi201745g (DOI)000298907400016 ()22133042 (PubMedID)
Available from: 2013-01-09 Created: 2013-01-07 Last updated: 2022-02-24Bibliographically approved
Abelein, A., Lang, L., Lendel, C., Gräslund, A. & Danielsson, J. (2012). Transient small molecule interactions kinetically modulate amyloid beta peptide self-assembly. FEBS Letters, 586(22), 3991-3995
Open this publication in new window or tab >>Transient small molecule interactions kinetically modulate amyloid beta peptide self-assembly
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2012 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, no 22, p. 3991-3995Article in journal (Refereed) Published
Abstract [en]

Small organic molecules, like Congo red and lacmoid, have been shown to modulate the self-assembly of the amyloid beta peptide (A beta). Here, we show that A beta forms NMR invisible non-toxic co-aggregates together with lacmoid as well as Congo red. We find that the interaction involves two distinct kinetic processes and at every given time point only a small fraction of A beta is in the co-aggregate. These weak transient interactions kinetically redirect the aggregation prone A beta from self-assembling into amyloid fibrils. These findings suggest that even such weak binders might be effective as therapeutics against pathogenic protein aggregation.

Keywords
Amyloid, Alzheimer's disease, NMR relaxation dispersion, Dynamic exchange
National Category
Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-83815 (URN)10.1016/j.febslet.2012.09.035 (DOI)000310783800010 ()
Note

AuthorCount:5;

Available from: 2012-12-14 Created: 2012-12-14 Last updated: 2022-02-24Bibliographically approved
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