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- Aisenbrey, Christopher, et al.
(author)
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How is protein aggregation in amyloidogenic diseases modulated by biological membranes?
- 2008
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In: European Biophysics Journal. - : SpringerLink. - 0175-7571 .- 1432-1017. ; 37:3, s. 247-55
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Journal article (peer-reviewed)abstract
- The fate of proteins with amyloidogenic properties depends critically on their immediate biochemical environment. However, the role of biological interfaces such as membrane surfaces, as promoters of pathological aggregation of amyloidogenic proteins, is rarely studied and only established for the amyloid-β protein (Aβ) involved in Alzheimer’s disease, and α-synuclein in Parkinsonism. The occurrence of binding and misfolding of these proteins on membrane surfaces, is poorly understood, not at least due to the two-dimensional character of this event. Clearly, the nature of the folding pathway for Aβ protein adsorbed upon two-dimensional aggregation templates, must be fundamentally different from the three-dimensional situation in solution. Here, we summarize the current research and focus on the function of membrane interfaces as aggregation templates for amyloidogenic proteins (and even prionic ones). One major aspect will be the relationship between membrane properties and protein association and the consequences for amyloidogenic products. The other focus will be on a general understanding of protein folding pathways on two-dimensional templates on a molecular level. Finally, we will demonstrate the potential importance of membrane-mediated aggregation for non-amphiphatic soluble amyloidogenic proteins, by using the SOD1 protein involved in the amyotrophic lateral sclerosis syndrome.
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| 5. |
- Bokvist, Marcus, 1975-
(author)
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Membrane mediated aggregation of amyloid-β protein : a potential key event in Alzheimer's disease
- 2007
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 6. |
- Bokvist, Marcus, et al.
(author)
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Misfolding of amyloidogenic proteins at membrane surfaces : the impact of macromolecularcCrowding
- 2007
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 129:48, s. 14848-14849
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Journal article (peer-reviewed)abstract
- The presence of inert macromolecular crowding agents mimics the situation in vivo where amyloidogenic proteins are released into an aqueous, congested intracellular environment. By using the amphiphatic Alzheimer A-protein as the model system, the presence of a three-dimensional macromolecular crowding environment enhanced significantly its misfolding behavior if charged membrane surfaces as two-dimensional aggregation templates were present.
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| 9. |
- Bokvist, Marcus, et al.
(author)
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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
- 2004
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In: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 335:4, s. 1039-1049
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Journal article (peer-reviewed)abstract
- 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.
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| 10. |
- Bonev, Boyan, et al.
(author)
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Electrostatic peptide-lipid interactions of amyloid-β peptide and pentalysine with membrane surfaces monitored by 31P MAS NMR
- 2001
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In: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 3:14, s. 2904-2910
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Journal article (peer-reviewed)abstract
- 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.
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