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Electrostatic peptide-lipid interactions of amyloid-β peptide and pentalysine with membrane surfaces monitored by 31P MAS NMR
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
2001 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, Vol. 3, no 14, 2904-2910 p.Article in journal (Refereed) Published
Abstract [en]

High-resolution 31P magic angle spinning (MAS) NMR spectroscopy is presented as a direct and non-perturbing method for measuring changes in surface charge density occurring in mixed phospholipid membranes upon binding of charged surface-active peptides. 31P MAS NMR was used to investigate mixed lipid membranes of neutral phosphatidylcholine and negatively charged phosphatidylglycerol where the molar fraction of the charged lipid was varied from 0 to 1. The chemical shifts of the  individual membrane lipids showed a simple variation in response to changes in the fraction of the negatively charged component phosphatidylglycerol. Addition of the positively charged amyloid-β1-40 peptide, a key substance in Alzheimer's disease, resulted in changes in the isotropic chemical shifts of the membrane lipid phosphates in a way consistent with reduction in the negative surface charge of the mixed lipid bilayers. Binding of different amounts of the positively charged peptide pentalysine to L-α-dioleoylphosphatidylcholine/L-α-dioleoylphosphatidylglycerol(DOPC/DOPG) vesicles (2 : 1 molar ratio) also showed a systematic variation of both chemical shift values. These changes were described by a simple two-site model and indicate purely electrostatic binding of pentalysine.

Place, publisher, year, edition, pages
2001. Vol. 3, no 14, 2904-2910 p.
Identifiers
URN: urn:nbn:se:umu:diva-5646DOI: 10.1039/b103352mOAI: oai:DiVA.org:umu-5646DiVA: diva2:145231
Available from: 2007-01-16 Created: 2007-01-16 Last updated: 2009-09-07Bibliographically approved
In thesis
1. Membrane mediated aggregation of amyloid-β protein: a potential key event in Alzheimer's disease
Open this publication in new window or tab >>Membrane mediated aggregation of amyloid-β protein: a potential key event in Alzheimer's disease
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pathogenesis of Alzheimer’s disease (AD), the most common senile dementia, is a complex process. A crucial event in AD is the aggregation of amyloid-β protein (Aβ), a cleavage product from the Amyloid Precursor Protein (APP). Aβ40, a common component in amyloid plaques found in patients, aggregates in vitro at concentrations, much higher than the one found in vivo. But in the presence of charged lipid membranes, aggregations occurs at much lower concentration in vitro compared to the membrane-free case. This can be understood due to the ability of Aβ to get electrostatically attracted to target membranes with a pronounced surface potential. This electrostatically driven process accumulates peptide at the membrane surface at concentrations high enough for aggregation while the bulk concentration still remains below threshold. Here, we elucidated the molecular nature of this Aβ-membrane process and its consequences for Aβ misfolding by Circular Dichroism Spectroscopy, Differential Scanning Calorimetry and Nuclear Magnetic Resonance Spectroscopy. First, we revealed by NMR that Aβ40 peptide does indeed interact electrostatically with membranes of negative and positive surface potential. Surprisingly, it even binds to nominal neutral membranes if these contain lipids of opposite charge. Combined NMR and CD studies also revealed that the peptide might be shielded from aggregation when incorporated into the membrane. Moreover, CD studies of Aβ40 added to charged membranes showed that both positively and negatively membranes induce aggregation albeit at different kinetics and finally that macromolecular crowding can both speed up and slow down aggregation of Aβ.

Place, publisher, year, edition, pages
Umeå: Kemi, 2007. 44 p.
Keyword
Alzheimer’s Disease, Aβ40, Circular Dichroism, NMR, Amyloids, Crowding, Peptide-Lipid Interaction
National Category
Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-969 (URN)978-91-7264-236-2 (ISBN)
Public defence
2007-02-09, kb3a9, kbc, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2007-01-16 Created: 2007-01-16 Last updated: 2009-09-07Bibliographically approved

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Gröbner, Gerhard

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