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Two Types of Alzheimer’s β-Amyloid (1–40) Peptide Membrane Interactions: Aggregation Preventing Transmembrane Anchoring Versus Accelerated Surface Fibril Formation
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
2004 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 335, no 4, 1039-1049 p.Article in journal (Refereed) Published
Abstract [en]

The 39–42 amino acid long, amphipathic amyloid-β peptide (Aβ) is one of the key components involved in Alzheimer's disease (AD). In the neuropathology of AD, Aβ presumably exerts its neurotoxic action via interactions with neuronal membranes. In our studies a combination of 31P MAS NMR (magic angle spinning nuclear magnetic resonance) and CD (circular dichroism) spectroscopy suggest fundamental differences in the functional organization of supramolecular Aβ1–40 membrane assemblies for two different scenarios with potential implication in AD: Aβ peptide can either be firmly anchored in a membrane upon proteolytic cleavage, thereby being prevented against release and aggregation, or it can have fundamentally adverse effects when bound to membrane surfaces by undergoing accelerated aggregation, causing neuronal apoptotic cell death. Acidic lipids can prevent release of membrane inserted Aβ1–40 by stabilizing its hydrophobic transmembrane C-terminal part (residue 29–40) in an α-helical conformation via an electrostatic anchor between its basic Lys28 residue and the negatively charged membrane interface. However, if Aβ1–40 is released as a soluble monomer, charged membranes act as two-dimensional aggregation-templates where an increasing amount of charged lipids (possible pathological degradation products) causes a dramatic accumulation of surface-associated Aβ1–40 peptide followed by accelerated aggregation into toxic structures. These results suggest that two different molecular mechanisms of peptide–membrane assemblies are involved in Aβ′s pathophysiology with the finely balanced type of Aβ–lipid interactions against release of Aβ from neuronal membranes being overcompensated by an Aβ–membrane assembly which causes toxic β-structured aggregates in AD. Therefore, pathological interactions of Aβ peptide with neuronal membranes might not only depend on the oligomerization state of the peptide, but also the type and nature of the supramolecular Aβ–membrane assemblies inherited from Aβ′s origin.

Place, publisher, year, edition, pages
2004. Vol. 335, no 4, 1039-1049 p.
Keyword [en]
lipid-membrane, β-amyloid peptide, peptide insertion, dircular dichroism, 31P MAS NMR
Identifiers
URN: urn:nbn:se:umu:diva-5201DOI: 10.1016/j.jmb.2003.11.046OAI: oai:DiVA.org:umu-5201DiVA: diva2:144619
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Biological membrane interfaces involved in diseases: a biophysical study
Open this publication in new window or tab >>Biological membrane interfaces involved in diseases: a biophysical study
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Interactions between peptides and biological lipid membranes play a crucial role in many cellular processes such as in the mechanism behind Alzheimer’s disease where amyloid-beta peptide (Abeta)is thought to be a key component. The initial step of binding between a surface active peptide and its target membrane or membrane receptor can involve a non specific electrostatic association where positively charged amino acid residues and a negatively charged membrane surface interact. Here, the use of high resolution MAS NMR provides a highly sensitive and non perturbing way of studying the electrostatic potential present at lipid membrane surfaces and the changes resulting from the association of peptides. The interaction between pharmacologically relevant peptides and lipid membranes can also involve incorporation of the peptide into the membrane core and by complementing the NMR approach with differential scanning calorimetry (DSC) the hydrophobic incorporation can be studied in a non invasive way.

By using 14N MAS NMR on biological lipid systems for the first time, in addition to 31P, 2H NMR and differential scanning calorimetry (DSC), gives a full picture of the changes all along the phospholipid following interactions at the membrane interface region. Being able to

monitor the full length of the phospholipid enables us to differentiate between interactions related to either membrane surface association or hydrophobic core incorporation. This approach was used to establish that the interaction between nociceptin and negatively charged lipid membranes is electrostatic and hence that nociceptin can initially associate with a membrane surface before binding to its receptor. Also, it was found that Abeta can interact with phospholipid membranes via two types of interactions with fundamentally adverse effects. The results reveal that Abeta can associate with the surface of a neuronal membrane promoting accelerated aggregation of the peptide leading to neuronal apoptotic cell death. Furthermore it is also shown that Abeta can anchor itself into the membrane and suppress the neurotoxic aggregation of Abeta.

Place, publisher, year, edition, pages
Umeå: Kemi, 2006. 50 p.
Keyword
Solid-state NMR, DSC, Amyloid-beta peptide, Nociceptin, DMPC, DMPG, DDAB, peptide-lipid interaction, branched-chain fatty acid.
National Category
Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-806 (URN)91-7264-080-4 (ISBN)
Public defence
2006-09-15, KB3A9, KBC-huset, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2009-09-07Bibliographically approved
2. 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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