Reactive microgliosis participates in MPP+-induced dopaminergic neurodegeneration: Role of 67 kDa laminin receptor

Tongguang Wang, Wei Zhang, Zhong Pei, Michelle Block, Belinda Wilson, Jeffrey M. Reece, David S. Miller, Jau Shyong Hong

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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 neuronmicroglia 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.

Original languageEnglish (US)
Pages (from-to)906-915
Number of pages10
JournalFASEB Journal
Volume20
Issue number7
DOIs
StatePublished - May 1 2006

Keywords

  • Extracellular matrix
  • Laminin receptor
  • MPP
  • Microglia
  • Neuron
  • Parkinson's disease

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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