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Modulation of amyloid β peptide self-assembly: Aggregation mechanisms associated with Alzheimer's disease
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2013 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University , 2013. , 22 p.
National Category
Biophysics
Research subject
Biophysics
Identifiers
URN: urn:nbn:se:su:diva-89078OAI: oai:DiVA.org:su-89078DiVA: diva2:615510
Presentation
2013-04-09, Magnéli hall, 14:30 (English)
Opponent
Supervisors
Available from: 2013-04-10 Created: 2013-04-10 Last updated: 2015-02-23Bibliographically approved
List of papers
1. Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid β self-assembly
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, 126-137 p.Article 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: 2017-12-06Bibliographically approved
2. Transient small molecule interactions kinetically modulate amyloid beta peptide self-assembly
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, 3991-3995 p.Article 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.

Keyword
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: 2017-12-06Bibliographically approved
3. Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates
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, 23518-23528 p.Article 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: 2017-12-06Bibliographically approved

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