Abstract
The role of first-stage β–amyloid aggregation in the development of the Alzheimer disease, is widely accepted but still unclear. Intimate interaction with the cell membrane is invoked. We designed Neutron Reflectometry experiments to reveal the existence and extent of the interaction between β–amyloid (Aβ) peptides and a lone customized biomimetic membrane, and their dependence on the aggregation state of the peptide. The membrane, asymmetrically containing phospholipids, GM1 and cholesterol in biosimilar proportion, is a model for a raft, a putative site for amyloid-cell membrane interaction. We found that the structured-oligomer of Aβ(1-42), its most acknowledged membrane-active state, is embedded as such into the external leaflet of the membrane. Conversely, the Aβ(1-42) unstructured early-oligomers deeply penetrate the membrane, likely mimicking the interaction at neuronal cell surfaces, when the Aβ(1-42) is cleaved from APP protein and the membrane constitutes a template for its further structural evolution. Moreover, the smaller Aβ(1-6) fragment, the N-terminal portion of Aβ, was also used. Aβ N-terminal is usually considered as involved in oligomer stabilization but not in the peptide-membrane interaction. Instead, it was seen to remove lipids from the bilayer, thus suggesting its role, once in the whole peptide, in membrane leakage, favouring peptide recruitment.
Highlights
Valeria Rondelli1, Paola Brocca1, Simona Motta1, Massimo Messa2, Laura Colombo2, Mario Salmona2, Giovanna Fragneto3, Laura Cantù1 & Elena Del Favero1
The mechanisms underlying Alzheimer’s Disease (AD) are not completely understood, but genetic, pathological and biochemical observations indicate that the progressive production and accumulation of β-amyloid peptides (Aβ), proteolytic fragments of the membrane-associated amyloid precursor protein (APP), play a pivotal role1
The interaction sites for either APP or Aβ are localized at those domains, such as rafts and caveolae12, enriched in cholesterol and GM1-ganglioside13–15
Summary
The mechanisms underlying Alzheimer’s Disease (AD) are not completely understood, but genetic, pathological and biochemical observations indicate that the progressive production and accumulation of β-amyloid peptides (Aβ), proteolytic fragments of the membrane-associated amyloid precursor protein (APP), play a pivotal role. The mechanisms underlying Alzheimer’s Disease (AD) are not completely understood, but genetic, pathological and biochemical observations indicate that the progressive production and accumulation of β-amyloid peptides (Aβ), proteolytic fragments of the membrane-associated amyloid precursor protein (APP), play a pivotal role1 Neurons release these peptides in a soluble form that progressively generates different molecular assemblies from oligomeric to multimeric structures, ending up to fibrillar aggregates. It has been reported that interaction with Aβ peptide modifies the morphology and mechanical properties of mixed model membranes containing cholesterol and sphingomyelin, depending on cholesterol content. The contrast variation strategy, exploiting the different cross-section of Hydrogen and Deuterium nuclei to a neutron beam, allows to enhance the visibility of an H-containing peptide in interaction with a fully-deuterated D-phospholipid membrane
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