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Microglia Acquire Distinct Activation Profiles Depending on the Degree of alpha-Synuclein Neuropathology in a rAAV Based Model of Parkinson's Disease

Sanchez-Guajardo, Vanesa; Febbraro, Fabia; Kirik, Deniz LU and Romero-Ramos, Marina LU (2010) In PLoS ONE 5(1).
Abstract
Post-mortem analysis of brains from Parkinson's disease (PD) patients strongly supports microglia activation and adaptive immunity as factors contributing to disease progression. Such responses may be triggered by alpha-synuclein (alpha-syn), which is known to be the main constituent of the aggregated proteins found in Lewy bodies in the brains of PD patients. To investigate this we used a recombinant viral vector to express human alpha-syn in rat midbrain at levels that induced neuronal pathology either in the absence or the presence of dopaminergic cell death, thereby mimicking early or late stages of the disease. Microglia activation was assessed by stereological quantification of Mac1+ cells, as well as the expression patterns of CD68... (More)
Post-mortem analysis of brains from Parkinson's disease (PD) patients strongly supports microglia activation and adaptive immunity as factors contributing to disease progression. Such responses may be triggered by alpha-synuclein (alpha-syn), which is known to be the main constituent of the aggregated proteins found in Lewy bodies in the brains of PD patients. To investigate this we used a recombinant viral vector to express human alpha-syn in rat midbrain at levels that induced neuronal pathology either in the absence or the presence of dopaminergic cell death, thereby mimicking early or late stages of the disease. Microglia activation was assessed by stereological quantification of Mac1+ cells, as well as the expression patterns of CD68 and MCH II. In our study, when alpha-syn induced neuronal pathology but not cell death, a fast transient increase in microglia cell numbers resulted in the long-term induction of MHC II+ microglia, denoting antigen-presenting ability. On the other hand, when alpha-syn induced both neuronal pathology and cell death, there was a delayed increase in microglia cell numbers, which correlated with long-lasting CD68 expression and a morphology reminiscent of peripheral macrophages. In addition T-lymphocyte infiltration, as judged by the presence of CD4+ and CD8+ cells, showed distinct kinetics depending on the degree of neurodegeneration, and was significantly higher when cell death occurred. We have thus for the first time shown that the microglial response differs depending on whether alpha-syn expression results on cell death or not, suggesting that microglia may play different roles during disease progression. Furthermore, our data suggest that the microglial response is modulated by early events related to alpha-syn expression in substantia nigra and persists at the long term. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
5
issue
1
publisher
Public Library of Science
external identifiers
  • wos:000273779000013
  • scopus:77649294300
ISSN
1932-6203
DOI
10.1371/journal.pone.0008784
language
English
LU publication?
yes
id
9a1fa970-746f-4e19-8691-b69ca6b92ca9 (old id 1547187)
date added to LUP
2010-02-24 09:57:09
date last changed
2018-05-29 11:02:25
@article{9a1fa970-746f-4e19-8691-b69ca6b92ca9,
  abstract     = {Post-mortem analysis of brains from Parkinson's disease (PD) patients strongly supports microglia activation and adaptive immunity as factors contributing to disease progression. Such responses may be triggered by alpha-synuclein (alpha-syn), which is known to be the main constituent of the aggregated proteins found in Lewy bodies in the brains of PD patients. To investigate this we used a recombinant viral vector to express human alpha-syn in rat midbrain at levels that induced neuronal pathology either in the absence or the presence of dopaminergic cell death, thereby mimicking early or late stages of the disease. Microglia activation was assessed by stereological quantification of Mac1+ cells, as well as the expression patterns of CD68 and MCH II. In our study, when alpha-syn induced neuronal pathology but not cell death, a fast transient increase in microglia cell numbers resulted in the long-term induction of MHC II+ microglia, denoting antigen-presenting ability. On the other hand, when alpha-syn induced both neuronal pathology and cell death, there was a delayed increase in microglia cell numbers, which correlated with long-lasting CD68 expression and a morphology reminiscent of peripheral macrophages. In addition T-lymphocyte infiltration, as judged by the presence of CD4+ and CD8+ cells, showed distinct kinetics depending on the degree of neurodegeneration, and was significantly higher when cell death occurred. We have thus for the first time shown that the microglial response differs depending on whether alpha-syn expression results on cell death or not, suggesting that microglia may play different roles during disease progression. Furthermore, our data suggest that the microglial response is modulated by early events related to alpha-syn expression in substantia nigra and persists at the long term.},
  author       = {Sanchez-Guajardo, Vanesa and Febbraro, Fabia and Kirik, Deniz and Romero-Ramos, Marina},
  issn         = {1932-6203},
  language     = {eng},
  number       = {1},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Microglia Acquire Distinct Activation Profiles Depending on the Degree of alpha-Synuclein Neuropathology in a rAAV Based Model of Parkinson's Disease},
  url          = {http://dx.doi.org/10.1371/journal.pone.0008784},
  volume       = {5},
  year         = {2010},
}