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Microglial activation and recruitment, but not proliferation, suffice to mediate neurodegeneration
A D Rogove1, W Lu, Stella E Tsirka
1Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA.
Abstract:
Microglial activation occurs during excitotoxin-induced neurodegeneration. We have reported that microglia can exhibit neurotoxic behaviors after injection of excitotoxins into the hippocampus. It is not known, however, whether microglial proliferation, which is part of the activation response, is required for neurodegeneration to be observed, or whether activation of the pre-existing resident microglia suffices. Using osteopetrotic (op/op) mice, in which injury-induced microglial proliferation does not take place, we demonstrate that only the microglia initially residing in the CNS are adequate to promote neurodegeneration. Our data suggest that there is a threshold at which a maximal microglial contribution to neurotoxicity is observed. This threshold appears to be sufficiently low, such that activation of just 40% of the microglia present in wild-type mice serves to trigger neurodegeneration. Furthermore, since the decrease in microglial numbers coincides with a decrease in tissue plasminogen activator's activity, we suggest that tissue plasminogen activator can be used as a marker for microglial proliferation.
Insights
Microglial proliferation is not required for excitotoxin-induced neurodegeneration. Resident microglia alone are sufficient to cause neurotoxicity, suggesting a low activation threshold for neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
Background:
- Microglial activation is observed during excitotoxin-induced neurodegeneration.
- The role of microglial proliferation versus activation of resident microglia in neurodegeneration remains unclear.
Purpose of the Study:
- To investigate whether microglial proliferation is essential for excitotoxin-induced neurodegeneration.
- To determine if activation of resident microglia is sufficient to cause neurotoxicity.
Main Methods:
- Utilized osteopetrotic (op/op) mice, which exhibit impaired microglial proliferation following injury.
- Administered excitotoxins into the hippocampus of these mice to study neurodegeneration.
Main Results:
- Osteopetrotic mice, lacking microglial proliferation, still exhibited neurodegeneration mediated by resident microglia.
- A threshold of approximately 40% microglial activation in wild-type mice was sufficient to trigger maximal neurotoxicity.
- A correlation was observed between decreased microglial numbers and reduced tissue plasminogen activator activity.
Conclusions:
- Microglial proliferation is not a prerequisite for excitotoxin-induced neurodegeneration.
- Resident microglia are sufficient to drive neurotoxicity, indicating a low threshold for this process.
- Tissue plasminogen activator activity may serve as a marker for microglial proliferation during neurodegeneration.