Cargando…

Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity

BACKGROUND: β-Amyloid peptide (Aβ) is a major protein in the brain associated with Alzheimer's and Parkinson's diseases. The purpose of this study was to investigate the role of macrophage antigen-1 (MAC1) receptor, an integrin scavenger receptor in microglia, and subsequent signaling even...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Dan, Hu, Xiaoming, Qian, Li, Chen, Shih-Heng, Zhou, Hui, Wilson, Belinda, Miller, David S, Hong, Jau-Shyong
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027117/
https://www.ncbi.nlm.nih.gov/pubmed/21232086
http://dx.doi.org/10.1186/1742-2094-8-3
_version_ 1782197122476539904
author Zhang, Dan
Hu, Xiaoming
Qian, Li
Chen, Shih-Heng
Zhou, Hui
Wilson, Belinda
Miller, David S
Hong, Jau-Shyong
author_facet Zhang, Dan
Hu, Xiaoming
Qian, Li
Chen, Shih-Heng
Zhou, Hui
Wilson, Belinda
Miller, David S
Hong, Jau-Shyong
author_sort Zhang, Dan
collection PubMed
description BACKGROUND: β-Amyloid peptide (Aβ) is a major protein in the brain associated with Alzheimer's and Parkinson's diseases. The purpose of this study was to investigate the role of macrophage antigen-1 (MAC1) receptor, an integrin scavenger receptor in microglia, and subsequent signaling events in mediating Aβ-induced neurotoxicity. We have previously reported that NADPH oxidase (PHOX) on microglia and superoxide produced by PHOX are critical for Aβ-induced loss of dopaminergic neurons. However, the upstream signaling pathway of superoxide production remains unclear. METHODS: For the in vitro study, mesencephalic neuron-glia cultures and microglia-enriched cultures from mice deficient in the MAC1 receptor (MAC1(-/-)) and wild type controls were used to investigate the role of MAC1 receptor in Aβ-induced neurotoxicity and the role of phosphoinositide-3 kinase (PI3K) in the signal pathway between MAC1 receptor and PHOX. For the in vivo study, Aβ was injected into the substantia nigra of MAC1(-/- )mice and wild type mice to confirm the role of MAC1 receptor. RESULTS: We found that Aβ-induced activation of microglia, activation of PHOX, generation of superoxide and other reactive oxygen species, and loss of dopaminergic neurons were decreased in MAC1(-/- )cultures compared to MAC1(+/+ )cultures. In MAC1(-/- )mice, dopaminergic neuron loss in response to Aβ injection into the substantia nigra was reduced relative to MAC1(+/+ )mice. Thus, MAC1 receptor-mediated PHOX activation and increased superoxide production are associated with Aβ-induced neurotoxicity. PI3K activation was one downstream step in MAC1 signaling to PHOX and played an important role in Aβ-induced neurotoxicity. In microglia-enriched cultures from MAC1(-/- )mice, Aβ-induced activation of PI3K (phosphorylation of target proteins and PIP(3 )production) was reduced relative to MAC1(+/+ )cultures. CONCLUSIONS: Taken together, our data demonstrate that Aβ activates MAC1 receptor to increase the activity of PI3K, which in turn phosphorylates p47(phox), triggers the translocation of cytosolic subunits of PHOX to microglia membrane, increases PHOX activation and the subsequent production of superoxide and causes neurotoxicity.
format Text
id pubmed-3027117
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-30271172011-01-27 Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity Zhang, Dan Hu, Xiaoming Qian, Li Chen, Shih-Heng Zhou, Hui Wilson, Belinda Miller, David S Hong, Jau-Shyong J Neuroinflammation Research BACKGROUND: β-Amyloid peptide (Aβ) is a major protein in the brain associated with Alzheimer's and Parkinson's diseases. The purpose of this study was to investigate the role of macrophage antigen-1 (MAC1) receptor, an integrin scavenger receptor in microglia, and subsequent signaling events in mediating Aβ-induced neurotoxicity. We have previously reported that NADPH oxidase (PHOX) on microglia and superoxide produced by PHOX are critical for Aβ-induced loss of dopaminergic neurons. However, the upstream signaling pathway of superoxide production remains unclear. METHODS: For the in vitro study, mesencephalic neuron-glia cultures and microglia-enriched cultures from mice deficient in the MAC1 receptor (MAC1(-/-)) and wild type controls were used to investigate the role of MAC1 receptor in Aβ-induced neurotoxicity and the role of phosphoinositide-3 kinase (PI3K) in the signal pathway between MAC1 receptor and PHOX. For the in vivo study, Aβ was injected into the substantia nigra of MAC1(-/- )mice and wild type mice to confirm the role of MAC1 receptor. RESULTS: We found that Aβ-induced activation of microglia, activation of PHOX, generation of superoxide and other reactive oxygen species, and loss of dopaminergic neurons were decreased in MAC1(-/- )cultures compared to MAC1(+/+ )cultures. In MAC1(-/- )mice, dopaminergic neuron loss in response to Aβ injection into the substantia nigra was reduced relative to MAC1(+/+ )mice. Thus, MAC1 receptor-mediated PHOX activation and increased superoxide production are associated with Aβ-induced neurotoxicity. PI3K activation was one downstream step in MAC1 signaling to PHOX and played an important role in Aβ-induced neurotoxicity. In microglia-enriched cultures from MAC1(-/- )mice, Aβ-induced activation of PI3K (phosphorylation of target proteins and PIP(3 )production) was reduced relative to MAC1(+/+ )cultures. CONCLUSIONS: Taken together, our data demonstrate that Aβ activates MAC1 receptor to increase the activity of PI3K, which in turn phosphorylates p47(phox), triggers the translocation of cytosolic subunits of PHOX to microglia membrane, increases PHOX activation and the subsequent production of superoxide and causes neurotoxicity. BioMed Central 2011-01-13 /pmc/articles/PMC3027117/ /pubmed/21232086 http://dx.doi.org/10.1186/1742-2094-8-3 Text en Copyright ©2011 Zhang 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
Zhang, Dan
Hu, Xiaoming
Qian, Li
Chen, Shih-Heng
Zhou, Hui
Wilson, Belinda
Miller, David S
Hong, Jau-Shyong
Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity
title Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity
title_full Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity
title_fullStr Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity
title_full_unstemmed Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity
title_short Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity
title_sort microglial mac1 receptor and pi3k are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027117/
https://www.ncbi.nlm.nih.gov/pubmed/21232086
http://dx.doi.org/10.1186/1742-2094-8-3
work_keys_str_mv AT zhangdan microglialmac1receptorandpi3kareessentialinmediatingbamyloidpeptideinducedmicroglialactivationandsubsequentneurotoxicity
AT huxiaoming microglialmac1receptorandpi3kareessentialinmediatingbamyloidpeptideinducedmicroglialactivationandsubsequentneurotoxicity
AT qianli microglialmac1receptorandpi3kareessentialinmediatingbamyloidpeptideinducedmicroglialactivationandsubsequentneurotoxicity
AT chenshihheng microglialmac1receptorandpi3kareessentialinmediatingbamyloidpeptideinducedmicroglialactivationandsubsequentneurotoxicity
AT zhouhui microglialmac1receptorandpi3kareessentialinmediatingbamyloidpeptideinducedmicroglialactivationandsubsequentneurotoxicity
AT wilsonbelinda microglialmac1receptorandpi3kareessentialinmediatingbamyloidpeptideinducedmicroglialactivationandsubsequentneurotoxicity
AT millerdavids microglialmac1receptorandpi3kareessentialinmediatingbamyloidpeptideinducedmicroglialactivationandsubsequentneurotoxicity
AT hongjaushyong microglialmac1receptorandpi3kareessentialinmediatingbamyloidpeptideinducedmicroglialactivationandsubsequentneurotoxicity