期刊
BRAIN PATHOLOGY
卷 21, 期 3, 页码 279-297出版社
WILEY
DOI: 10.1111/j.1750-3639.2010.00445.x
关键词
chemokines; microglia activation; neurodegeneration; oxidative stress; thiamine deficiency
资金
- Ministry of Science and Technology of China [2010CB912000, 2007CB947100]
- National Natural Science Foundation of China [30870812, 30570580]
- Chinese Academy of Sciences [KSCX2-YW-R-115, 07DJ14005]
- Shanghai Institutes for Biological Sciences
- Shanghai Pujiang Program
- NIH/NIAAA [AA015407]
Chemokines are implicated in the neuroinflammation of several chronic neurodegenerative disorders. However, the precise role of chemokines in neurodegeneration is unknown. Thiamine deficiency (TD) causes abnormal oxidative metabolism in the brain as well as a well-defined microglia activation and neurodegeneration in the submedial thalamus nucleus (SmTN), which are common features of neurodegenerative diseases. We evaluated the role of chemokines in neurodegeneration and the underlying mechanism in a TD model. Among the chemokines examined, TD selectively induced neuronal expression of monocyte chemoattractant protein-1 (MCP-1) in the SmTN prior to microglia activation and neurodegeneration. The conditioned medium collected from TD-induced neurons caused microglia activation. With a neuron/microglia co-culture system, we showed that MCP-1-induced neurotoxicity required the presence of microglia, and exogenous MCP-1 was able to activate microglia and stimulated microglia to produce cytokines. A MCP-1 neutralizing antibody inhibited MCP-1-induced microglia activation and neuronal death in culture and in the thalamus. MCP-1 knockout mice were resistant to TD-induced neuronal death in SmTN. TD selectively induced the accumulation of reactive oxygen species in neurons, and antioxidants blocked TD-induced MCP-1 expression. Together, our results indicated an induction of neuronal MCP-1 during mild impairment of oxidative metabolism caused by microglia recruitment/activation, which exacerbated neurodegeneration.
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