Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy.
The role of microglial activation in multiple system atrophy (MSA) was investigated in a transgenic mouse model featuring oligodendroglial alpha-synuclein inclusions and loss of midbrain dopaminergic neurons by means of histopathology and morphometric analysis. Our findings demonstrate early progressive microglial activation in substantia nigra pars compacta (SNc) associated with increased expression of iNOS and correlating with dopaminergic neuronal loss. Suppression of microglial activation by early long-term minocycline treatment protected dopaminergic SNc neurons. The results suggest that oligodendroglial overexpression of alpha-synuclein may induce neuroinflammation related to nitrosive stress which is likely to contribute to neurodegeneration in MSA. Further, we detected increased toll-like receptor 4 immunoreactivity in both transgenic mice and MSA brains indicating a possible signaling pathway in MSA which needs to be further studied as a candidate target for neuroprotective interventions.
Stefanova
Nadia
N
Clinical Neurobiology Unit, Neurodegeneration Research Laboratory, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Reindl
Markus
M
Neumann
Manuela
M
Kahle
Philipp J
PJ
Poewe
Werner
W
Wenning
Gregor K
GK
D000368:Aged; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004298:Dopamine / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology*; D008875:Middle Aged; D008911:Minocycline / Q000494:pharmacology; D019578:Multiple System Atrophy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D018696:Neuroprotective Agents; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051844:alpha-Synuclein; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008911:Minocycline; D004298:Dopamine