Point Mutations in Aβ Result in the Formation of Distinct Polymorphic Aggregates in the Presence of Lipid Bilayers
A hallmark of Alzheimer's disease (AD) is the rearrangement of the β-amyloid (Aβ) peptide to a non-native conformation that promotes the formation of toxic, nanoscale aggregates. Recent studies have pointed to the role of sample preparation in creating polymorphic fibrillar species. One of many...
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ftwestvirginiaun:oai:researchrepository.wvu.edu:faculty_publications-3688 2023-05-15T15:13:36+02:00 Point Mutations in Aβ Result in the Formation of Distinct Polymorphic Aggregates in the Presence of Lipid Bilayers Pifer, Phillip M Yates, Elizabeth A Legleiter, Justin 2011-01-01T08:00:00Z application/pdf https://researchrepository.wvu.edu/faculty_publications/2793 https://researchrepository.wvu.edu/cgi/viewcontent.cgi?article=3688&context=faculty_publications unknown The Research Repository @ WVU https://researchrepository.wvu.edu/faculty_publications/2793 https://researchrepository.wvu.edu/cgi/viewcontent.cgi?article=3688&context=faculty_publications Faculty & Staff Scholarship Point mutation Oligomers Italian people Lipid bilayer Lipids Lipid structure Membrane potential Lipid aggregates text 2011 ftwestvirginiaun 2022-01-05T11:51:10Z A hallmark of Alzheimer's disease (AD) is the rearrangement of the β-amyloid (Aβ) peptide to a non-native conformation that promotes the formation of toxic, nanoscale aggregates. Recent studies have pointed to the role of sample preparation in creating polymorphic fibrillar species. One of many potential pathways for Aβ toxicity may be modulation of lipid membrane function on cellular surfaces. There are several mutations clustered around the central hydrophobic core of Aβ near the α-secretase cleavage site (E22G Arctic mutation, E22K Italian mutation, D23N Iowa mutation, and A21G Flemish mutation). These point mutations are associated with hereditary diseases ranging from almost pure cerebral amyloid angiopathy (CAA) to typical Alzheimer's disease pathology with plaques and tangles. We investigated how these point mutations alter Aβ aggregation in the presence of supported lipid membranes comprised of total brain lipid extract. Brain lipid extract bilayers were used as a physiologically relevant model of a neuronal cell surface. Intact lipid bilayers were exposed to predominantly monomeric preparations of Wild Type or different mutant forms of Aβ, and atomic force microscopy was used to monitor aggregate formation and morphology as well as bilayer integrity over a 12 hour period. The goal of this study was to determine how point mutations in Aβ, which alter peptide charge and hydrophobic character, influence interactions between Aβ and the lipid surface. While fibril morphology did not appear to be significantly altered when mutants were prepped similarly and incubated under free solution conditions, aggregation in the lipid membranes resulted in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also had a variable ability to disrupt bilayer integrity. Text Arctic The Research Repository @ WVU (West Virginia University) Arctic |
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Point mutation Oligomers Italian people Lipid bilayer Lipids Lipid structure Membrane potential Lipid aggregates |
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Point mutation Oligomers Italian people Lipid bilayer Lipids Lipid structure Membrane potential Lipid aggregates Pifer, Phillip M Yates, Elizabeth A Legleiter, Justin Point Mutations in Aβ Result in the Formation of Distinct Polymorphic Aggregates in the Presence of Lipid Bilayers |
topic_facet |
Point mutation Oligomers Italian people Lipid bilayer Lipids Lipid structure Membrane potential Lipid aggregates |
description |
A hallmark of Alzheimer's disease (AD) is the rearrangement of the β-amyloid (Aβ) peptide to a non-native conformation that promotes the formation of toxic, nanoscale aggregates. Recent studies have pointed to the role of sample preparation in creating polymorphic fibrillar species. One of many potential pathways for Aβ toxicity may be modulation of lipid membrane function on cellular surfaces. There are several mutations clustered around the central hydrophobic core of Aβ near the α-secretase cleavage site (E22G Arctic mutation, E22K Italian mutation, D23N Iowa mutation, and A21G Flemish mutation). These point mutations are associated with hereditary diseases ranging from almost pure cerebral amyloid angiopathy (CAA) to typical Alzheimer's disease pathology with plaques and tangles. We investigated how these point mutations alter Aβ aggregation in the presence of supported lipid membranes comprised of total brain lipid extract. Brain lipid extract bilayers were used as a physiologically relevant model of a neuronal cell surface. Intact lipid bilayers were exposed to predominantly monomeric preparations of Wild Type or different mutant forms of Aβ, and atomic force microscopy was used to monitor aggregate formation and morphology as well as bilayer integrity over a 12 hour period. The goal of this study was to determine how point mutations in Aβ, which alter peptide charge and hydrophobic character, influence interactions between Aβ and the lipid surface. While fibril morphology did not appear to be significantly altered when mutants were prepped similarly and incubated under free solution conditions, aggregation in the lipid membranes resulted in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also had a variable ability to disrupt bilayer integrity. |
format |
Text |
author |
Pifer, Phillip M Yates, Elizabeth A Legleiter, Justin |
author_facet |
Pifer, Phillip M Yates, Elizabeth A Legleiter, Justin |
author_sort |
Pifer, Phillip M |
title |
Point Mutations in Aβ Result in the Formation of Distinct Polymorphic Aggregates in the Presence of Lipid Bilayers |
title_short |
Point Mutations in Aβ Result in the Formation of Distinct Polymorphic Aggregates in the Presence of Lipid Bilayers |
title_full |
Point Mutations in Aβ Result in the Formation of Distinct Polymorphic Aggregates in the Presence of Lipid Bilayers |
title_fullStr |
Point Mutations in Aβ Result in the Formation of Distinct Polymorphic Aggregates in the Presence of Lipid Bilayers |
title_full_unstemmed |
Point Mutations in Aβ Result in the Formation of Distinct Polymorphic Aggregates in the Presence of Lipid Bilayers |
title_sort |
point mutations in aβ result in the formation of distinct polymorphic aggregates in the presence of lipid bilayers |
publisher |
The Research Repository @ WVU |
publishDate |
2011 |
url |
https://researchrepository.wvu.edu/faculty_publications/2793 https://researchrepository.wvu.edu/cgi/viewcontent.cgi?article=3688&context=faculty_publications |
geographic |
Arctic |
geographic_facet |
Arctic |
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Arctic |
op_source |
Faculty & Staff Scholarship |
op_relation |
https://researchrepository.wvu.edu/faculty_publications/2793 https://researchrepository.wvu.edu/cgi/viewcontent.cgi?article=3688&context=faculty_publications |
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