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Membrane mediated aggregation of amyloid-β protein: a potential key event in Alzheimer's disease
Umeå University, Faculty of Science and Technology, Chemistry.
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 [en]
Alzheimer’s Disease, Aβ40, Circular Dichroism, NMR, Amyloids, Crowding, Peptide-Lipid Interaction
National Category
Physical Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-969ISBN: 978-91-7264-236-2 (print)OAI: oai:DiVA.org:umu-969DiVA: diva2:145236
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
List of papers
1. Electrostatic peptide-lipid interactions of amyloid-β peptide and pentalysine with membrane surfaces monitored by 31P MAS NMR
Open this publication in new window or tab >>Electrostatic peptide-lipid interactions of amyloid-β peptide and pentalysine with membrane surfaces monitored by 31P MAS NMR
2001 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, 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.

Identifiers
urn:nbn:se:umu:diva-5646 (URN)10.1039/b103352m (DOI)
Available from: 2007-01-16 Created: 2007-01-16 Last updated: 2017-12-14Bibliographically approved
2. Association of amyloid-β peptide with membrane surfaces monitored by solid state NMR
Open this publication in new window or tab >>Association of amyloid-β peptide with membrane surfaces monitored by solid state NMR
2002 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 4, no 22, 5524-5530 p.Article in journal (Refereed) Published
Abstract [en]

Amyloid-β peptide (Aβ), a key substance in Alzheimers disease (AD), is characterized by its abnormal folding into neurotoxic aggregates. Since Aβ comprises an extracellular and transmembrane domain, some of its neurotoxic actions might be exerted via interactions with neuronal membranes. Wideline and magic angle spinning 14N and 31P NMR have been used in combination with differential scanning calorimetry and circular dichroism spectroscopy to investigate the association between Aβ1–40 peptide and membranes with different electrostatic surface potentials. Calorimetric measurements showed that all membrane systems were in the liquid crystalline state at 308 K. Binding of Aβ1–40 at a 30 1 lipid/peptide ratio to membranes composed of neutral dimyristoyl-phosphatidylcholine (DMPC) and negatively charged dimyristoylphosphatidylglycerol (DMPG) at a 4 : 1 molar ratio is mainly driven electrostatically, reflected in characteristic changes of the isotropic 31P chemical shift values for both lipids. In addition, the average orientation of the choline headgroup of DMPC, with its electric P–N+(CH3)3 dipole, changed directly in response to the reduced negative membrane surface potential. The deviation in tilt angle of the PN vector relative to the membrane surface is manifested in the observed 14N NMR quadrupole splitting and can therefore be described semiquantitatively. Adding Aβ1–40 to membranes with nominal neutral surface charge, but composed of a ternary mixture of DMPC with DMPG and the cationic amphiphile didodecyldimethyl–ammonium bromide (DDAB) at a 3 : 1 : 1 molar ratio revealed surprisingly electrostatic interactions visible in the NMR spectra. Since Aβ1–40 does not bind to neutral DMPC bilayers a model is proposed, in which on a molecular level the charged residues of Aβ1–40 peptide can interact independently with lipid headgroups of various charges in these microscopically heterogeneous systems.

Identifiers
urn:nbn:se:umu:diva-5647 (URN)10.1039/b206351d (DOI)
Available from: 2007-01-16 Created: 2007-01-16 Last updated: 2017-12-14Bibliographically approved
3. Two Types of Alzheimer’s β-Amyloid (1–40) Peptide Membrane Interactions: Aggregation Preventing Transmembrane Anchoring Versus Accelerated Surface Fibril Formation
Open this publication in new window or tab >>Two Types of Alzheimer’s β-Amyloid (1–40) Peptide Membrane Interactions: Aggregation Preventing Transmembrane Anchoring Versus Accelerated Surface Fibril Formation
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.

Keyword
lipid-membrane, β-amyloid peptide, peptide insertion, dircular dichroism, 31P MAS NMR
Identifiers
urn:nbn:se:umu:diva-5201 (URN)10.1016/j.jmb.2003.11.046 (DOI)
Available from: 2006-06-02 Created: 2006-06-02 Last updated: 2017-12-14Bibliographically approved
4. Two-dimensional aggregation of Alzheimer's β-amyloid (1-40) on membrane surfaces: two electrostatically controlled alternative pathways
Open this publication in new window or tab >>Two-dimensional aggregation of Alzheimer's β-amyloid (1-40) on membrane surfaces: two electrostatically controlled alternative pathways
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5649 (URN)
Available from: 2007-01-16 Created: 2007-01-16 Last updated: 2010-01-13Bibliographically approved
5. The impact of macromolecular crowding on the folding behaviour of amyloid-β protein at membrane surfaces
Open this publication in new window or tab >>The impact of macromolecular crowding on the folding behaviour of amyloid-β protein at membrane surfaces
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5650 (URN)
Available from: 2007-01-16 Created: 2007-01-16 Last updated: 2010-01-13Bibliographically approved

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