Membrane mediated aggregation of amyloid-β protein: a potential key event in Alzheimer's disease
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
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.
Alzheimer’s Disease, Aβ40, Circular Dichroism, NMR, Amyloids, Crowding, Peptide-Lipid Interaction
IdentifiersURN: urn:nbn:se:umu:diva-969ISBN: 978-91-7264-236-2OAI: oai:DiVA.org:umu-969DiVA: diva2:145236
2007-02-09, kb3a9, kbc, Umeå universitet, Umeå, 10:00 (English)
Mäler, Lena, Docent
Gröbner, Gerhard, DocentLindblom, Göran, Professor
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