Cargando…
Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation
Alzheimer’s disease (AD) is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-β (Aβ) peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contribut...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583148/ https://www.ncbi.nlm.nih.gov/pubmed/28912710 http://dx.doi.org/10.3389/fnagi.2017.00277 |
_version_ | 1783261263338405888 |
---|---|
author | Caldeira, Cláudia Cunha, Carolina Vaz, Ana R. Falcão, Ana S. Barateiro, Andreia Seixas, Elsa Fernandes, Adelaide Brites, Dora |
author_facet | Caldeira, Cláudia Cunha, Carolina Vaz, Ana R. Falcão, Ana S. Barateiro, Andreia Seixas, Elsa Fernandes, Adelaide Brites, Dora |
author_sort | Caldeira, Cláudia |
collection | PubMed |
description | Alzheimer’s disease (AD) is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-β (Aβ) peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contributor to disease pathogenesis; however, different microglia phenotypes were identified along AD progression and excessive Aβ production was shown to dysregulate cell function. As so, the contribution of microglia to AD pathogenesis remains to be elucidated. In this study, we wondered if isolated microglia cultured for 16 days in vitro (DIV) would react differentially from the 2 DIV cells upon treatment with 1000 nM Aβ(1–42) for 24 h. No changes in cell viability were observed and morphometric alterations associated to microglia activation, such as volume increase and process shortening, were obvious in 2 DIV microglia, but less evident in 16 DIV cells. These cells showed lower phagocytic, migration and autophagic properties after Aβ treatment than the 2 DIV cultured microglia. Reduced phagocytosis may derive from increased CD33 expression, reduced triggering receptor expressed on myeloid cells 2 (TREM2) and milk fat globule-EGF factor 8 protein (MFG-E8) levels, which were mainly observed in 16 DIV cells. Activation of inflammatory mediators, such as high mobility group box 1 (HMGB1) and pro-inflammatory cytokines, as well as increased expression of Toll-like receptor 2 (TLR2), TLR4 and fractalkine/CX3C chemokine receptor 1 (CX3CR1) cell surface receptors were prominent in 2 DIV microglia, while elevation of matrix metalloproteinase 9 (MMP9) was marked in 16 DIV cells. Increased senescence-associated β-galactosidase (SA-β-gal) and upregulated miR-146a expression that were observed in 16 DIV cells showed to increase by Aβ in 2 DIV microglia. Additionally, Aβ downregulated miR-155 and miR-124, and reduced the CD11b+ subpopulation in 2 DIV microglia, while increased the number of CD86+ cells in 16 DIV microglia. Simultaneous M1 and M2 markers were found after Aβ treatment, but at lower expression in the in vitro aged microglia. Data show key-aging associated responses by microglia when incubated with Aβ, with a loss of reactivity from the 2 DIV to the 16 DIV cells, which course with a reduced phagocytosis, migration and lower expression of inflammatory miRNAs. These findings help to improve our understanding on the heterogeneous responses that microglia can have along the progression of AD disease and imply that therapeutic approaches may differ from early to late stages. |
format | Online Article Text |
id | pubmed-5583148 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55831482017-09-14 Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation Caldeira, Cláudia Cunha, Carolina Vaz, Ana R. Falcão, Ana S. Barateiro, Andreia Seixas, Elsa Fernandes, Adelaide Brites, Dora Front Aging Neurosci Neuroscience Alzheimer’s disease (AD) is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-β (Aβ) peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contributor to disease pathogenesis; however, different microglia phenotypes were identified along AD progression and excessive Aβ production was shown to dysregulate cell function. As so, the contribution of microglia to AD pathogenesis remains to be elucidated. In this study, we wondered if isolated microglia cultured for 16 days in vitro (DIV) would react differentially from the 2 DIV cells upon treatment with 1000 nM Aβ(1–42) for 24 h. No changes in cell viability were observed and morphometric alterations associated to microglia activation, such as volume increase and process shortening, were obvious in 2 DIV microglia, but less evident in 16 DIV cells. These cells showed lower phagocytic, migration and autophagic properties after Aβ treatment than the 2 DIV cultured microglia. Reduced phagocytosis may derive from increased CD33 expression, reduced triggering receptor expressed on myeloid cells 2 (TREM2) and milk fat globule-EGF factor 8 protein (MFG-E8) levels, which were mainly observed in 16 DIV cells. Activation of inflammatory mediators, such as high mobility group box 1 (HMGB1) and pro-inflammatory cytokines, as well as increased expression of Toll-like receptor 2 (TLR2), TLR4 and fractalkine/CX3C chemokine receptor 1 (CX3CR1) cell surface receptors were prominent in 2 DIV microglia, while elevation of matrix metalloproteinase 9 (MMP9) was marked in 16 DIV cells. Increased senescence-associated β-galactosidase (SA-β-gal) and upregulated miR-146a expression that were observed in 16 DIV cells showed to increase by Aβ in 2 DIV microglia. Additionally, Aβ downregulated miR-155 and miR-124, and reduced the CD11b+ subpopulation in 2 DIV microglia, while increased the number of CD86+ cells in 16 DIV microglia. Simultaneous M1 and M2 markers were found after Aβ treatment, but at lower expression in the in vitro aged microglia. Data show key-aging associated responses by microglia when incubated with Aβ, with a loss of reactivity from the 2 DIV to the 16 DIV cells, which course with a reduced phagocytosis, migration and lower expression of inflammatory miRNAs. These findings help to improve our understanding on the heterogeneous responses that microglia can have along the progression of AD disease and imply that therapeutic approaches may differ from early to late stages. Frontiers Media S.A. 2017-08-31 /pmc/articles/PMC5583148/ /pubmed/28912710 http://dx.doi.org/10.3389/fnagi.2017.00277 Text en Copyright © 2017 Caldeira, Cunha, Vaz, Falcão, Barateiro, Seixas, Fernandes and Brites. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Caldeira, Cláudia Cunha, Carolina Vaz, Ana R. Falcão, Ana S. Barateiro, Andreia Seixas, Elsa Fernandes, Adelaide Brites, Dora Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation |
title | Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation |
title_full | Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation |
title_fullStr | Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation |
title_full_unstemmed | Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation |
title_short | Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation |
title_sort | key aging-associated alterations in primary microglia response to beta-amyloid stimulation |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583148/ https://www.ncbi.nlm.nih.gov/pubmed/28912710 http://dx.doi.org/10.3389/fnagi.2017.00277 |
work_keys_str_mv | AT caldeiraclaudia keyagingassociatedalterationsinprimarymicrogliaresponsetobetaamyloidstimulation AT cunhacarolina keyagingassociatedalterationsinprimarymicrogliaresponsetobetaamyloidstimulation AT vazanar keyagingassociatedalterationsinprimarymicrogliaresponsetobetaamyloidstimulation AT falcaoanas keyagingassociatedalterationsinprimarymicrogliaresponsetobetaamyloidstimulation AT barateiroandreia keyagingassociatedalterationsinprimarymicrogliaresponsetobetaamyloidstimulation AT seixaselsa keyagingassociatedalterationsinprimarymicrogliaresponsetobetaamyloidstimulation AT fernandesadelaide keyagingassociatedalterationsinprimarymicrogliaresponsetobetaamyloidstimulation AT britesdora keyagingassociatedalterationsinprimarymicrogliaresponsetobetaamyloidstimulation |