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Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia
BACKGROUND: Beta amyloid (Aβ) peptides are the major constituents of the senile plaques present in Alzheimer's diseased brain. Pathogenesis has been associated with the aggregated form of the peptide as these fibrils are the conformation readily found in the plaques. However, recent studies hav...
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632990/ https://www.ncbi.nlm.nih.gov/pubmed/19123954 http://dx.doi.org/10.1186/1742-2094-6-1 |
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author | Sondag, Cindy M Dhawan, Gunjan Combs, Colin K |
author_facet | Sondag, Cindy M Dhawan, Gunjan Combs, Colin K |
author_sort | Sondag, Cindy M |
collection | PubMed |
description | BACKGROUND: Beta amyloid (Aβ) peptides are the major constituents of the senile plaques present in Alzheimer's diseased brain. Pathogenesis has been associated with the aggregated form of the peptide as these fibrils are the conformation readily found in the plaques. However, recent studies have shown that the nonaggregated, soluble assemblies of Aβ have the potential to stimulate neuronal dysfunction and may play a prominent role in the pathogenesis of Alzheimer's disease. METHODS: Soluble, synthetic Aβ1–42 oligomers were prepared producing mainly dimer-trimer conformations as assessed by SDS-PAGE. Similar analysis demonstrated fibril preparations to produce large insoluble aggregates unable to migrate out of the stacking portion of the gels. These peptide preparations were used to stimulate primary murine microglia and cortical neuron cultures. Microglia were analyzed for changes in signaling response and secretory phenotype via Western analysis and ELISA. Viability was examined by quantifying lactate dehydrogenase release from the cultures. RESULTS: Aβ oligomers and fibrils were used to stimulate microglia for comparison. Both the oligomers and fibrils stimulated proinflammatory activation of primary microglia but the specific conformation of the peptide determined the activation profile. Oligomers stimulated increased levels of active, phosphorylated Lyn and Syk kinase as well as p38 MAP kinase compared to fibrils. Moreover, oligomers stimulated a differential secretory profile for interleukin 6, monocyte chemoattractant protein-1 and keratinocyte chemoattractant when compared to fibrils. Finally, soluble oligomers stimulated death of cultured cortical neurons that was exacerbated by the presence of microglia. CONCLUSION: These data suggest that fibrils and oligomers stimulate unique signaling responses in microglia leading to discrete secretory changes and effects on neuron survival. This suggests that inflammation changes during disease may be the consequence of unique peptide-stimulated events and each conformation may represent an individual anti-inflammatory therapeutic target. |
format | Text |
id | pubmed-2632990 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-26329902009-01-30 Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia Sondag, Cindy M Dhawan, Gunjan Combs, Colin K J Neuroinflammation Research BACKGROUND: Beta amyloid (Aβ) peptides are the major constituents of the senile plaques present in Alzheimer's diseased brain. Pathogenesis has been associated with the aggregated form of the peptide as these fibrils are the conformation readily found in the plaques. However, recent studies have shown that the nonaggregated, soluble assemblies of Aβ have the potential to stimulate neuronal dysfunction and may play a prominent role in the pathogenesis of Alzheimer's disease. METHODS: Soluble, synthetic Aβ1–42 oligomers were prepared producing mainly dimer-trimer conformations as assessed by SDS-PAGE. Similar analysis demonstrated fibril preparations to produce large insoluble aggregates unable to migrate out of the stacking portion of the gels. These peptide preparations were used to stimulate primary murine microglia and cortical neuron cultures. Microglia were analyzed for changes in signaling response and secretory phenotype via Western analysis and ELISA. Viability was examined by quantifying lactate dehydrogenase release from the cultures. RESULTS: Aβ oligomers and fibrils were used to stimulate microglia for comparison. Both the oligomers and fibrils stimulated proinflammatory activation of primary microglia but the specific conformation of the peptide determined the activation profile. Oligomers stimulated increased levels of active, phosphorylated Lyn and Syk kinase as well as p38 MAP kinase compared to fibrils. Moreover, oligomers stimulated a differential secretory profile for interleukin 6, monocyte chemoattractant protein-1 and keratinocyte chemoattractant when compared to fibrils. Finally, soluble oligomers stimulated death of cultured cortical neurons that was exacerbated by the presence of microglia. CONCLUSION: These data suggest that fibrils and oligomers stimulate unique signaling responses in microglia leading to discrete secretory changes and effects on neuron survival. This suggests that inflammation changes during disease may be the consequence of unique peptide-stimulated events and each conformation may represent an individual anti-inflammatory therapeutic target. BioMed Central 2009-01-05 /pmc/articles/PMC2632990/ /pubmed/19123954 http://dx.doi.org/10.1186/1742-2094-6-1 Text en Copyright © 2009 Sondag et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Sondag, Cindy M Dhawan, Gunjan Combs, Colin K Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia |
title | Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia |
title_full | Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia |
title_fullStr | Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia |
title_full_unstemmed | Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia |
title_short | Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia |
title_sort | beta amyloid oligomers and fibrils stimulate differential activation of primary microglia |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632990/ https://www.ncbi.nlm.nih.gov/pubmed/19123954 http://dx.doi.org/10.1186/1742-2094-6-1 |
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