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...
Published in: | PLoS ONE |
---|---|
Main Authors: | , , |
Format: | Text |
Language: | English |
Published: |
Public Library of Science
2011
|
Subjects: | |
Online Access: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022758 http://www.ncbi.nlm.nih.gov/pubmed/21267410 https://doi.org/10.1371/journal.pone.0016248 |
id |
ftpubmed:oai:pubmedcentral.nih.gov:3022758 |
---|---|
record_format |
openpolar |
spelling |
ftpubmed:oai:pubmedcentral.nih.gov:3022758 2023-05-15T15:13:35+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 2011-01-18 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022758 http://www.ncbi.nlm.nih.gov/pubmed/21267410 https://doi.org/10.1371/journal.pone.0016248 en eng Public Library of Science http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022758 http://www.ncbi.nlm.nih.gov/pubmed/21267410 http://dx.doi.org/10.1371/journal.pone.0016248 Pifer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. CC-BY Research Article Text 2011 ftpubmed https://doi.org/10.1371/journal.pone.0016248 2013-09-03T10:04:27Z 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 PubMed Central (PMC) Arctic PLoS ONE 6 1 e16248 |
institution |
Open Polar |
collection |
PubMed Central (PMC) |
op_collection_id |
ftpubmed |
language |
English |
topic |
Research Article |
spellingShingle |
Research Article 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 |
Research Article |
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 |
Public Library of Science |
publishDate |
2011 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022758 http://www.ncbi.nlm.nih.gov/pubmed/21267410 https://doi.org/10.1371/journal.pone.0016248 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022758 http://www.ncbi.nlm.nih.gov/pubmed/21267410 http://dx.doi.org/10.1371/journal.pone.0016248 |
op_rights |
Pifer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.1371/journal.pone.0016248 |
container_title |
PLoS ONE |
container_volume |
6 |
container_issue |
1 |
container_start_page |
e16248 |
_version_ |
1766344117142421504 |