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,1,2
* Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA;
Department of Hand Surgery, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China;
Confocal Microscopy Center, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA; and
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA
1Correspondence: E-mail: twang40{at}jhmi.edu
It has been reported that extracellular matrix (ECM) molecules regulate monocyte activation by binding with a 67 kDa nonintegrin laminin receptor (LR). As microgliosis is a pivotal factor in propelling the progress of chronic neurodegeneration in the brain, we hypothesized that LR may regulate the microgliosis and subsequent neurotoxicity. Using 1-methyl-4-phenylpyridinium (MPP+) -treated C57 mice primary mesencephalic neuron-glia cultures as an in vitro Parkinson’s disease (PD) model, we observed that MPP+ treatment increased LR expression only in the mixed neuron-glia but not in microglia-enriched or microglia-depleted cultures, indicating that MPP+-induced increase of LR expression is associated with neuron-microglia interaction. Using confocal microscopic examination, we found that LR was localized in the microglia, which were F4/80 positive. Treatment with the antibody (Ab) against LR (LR-Ab) or YIGSR, a synthetic pentapeptide inhibitor for LR, significantly attenuated the MPP+-increased F4/80 immunoreactivity (24 h) and dopaminergic (DA) neurotoxicity. LR-Ab also attenuated MPP+-increased microglial phagocytotic activity (48 h) and the superoxide production (4 days). Further study demonstrated that exogenous laminin (1–10 µg/ml) treatment induced microglial activation and DA neurotoxicity, in a dose-dependent manner, which was partially attenuated by the LR-Ab. We concluded that by regulating cell-ECM interaction, LR plays important roles in mediating microgliosis and subsequent DA neurotoxicity. Laminin is a potential ligand for activating this LR receptor. This study also suggests that laminin/LR is a potential target for developing new therapeutic drugs against neurodegenerative disorders such as PD.—Wang, T., Zhang, W., Pei, Z., Block, M., Wilson, B., Reece, J. M., Miller, D. S., and Hong, J.-S. Reactive microgliosis participates in MPP+-induced dopaminergic neurodegeneration: role of 67 kDa laminin receptor.
Key Words: laminin receptor • extracellular matrix • microglia • neuron • MPP+ • Parkinson’s disease
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