Journal
NEUROBIOLOGY OF AGING
Volume 30, Issue 11, Pages 1805-1817Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2008.01.001
Keywords
Microglia; Dopamine; Dopamine receptor; Parkinson's disease; Substantia nigra; Chemotaxis
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Funding
- NIH [AGO-7367]
- Arizona Alzheimer's Research Consortium (Arizona Department of Health Services) [211002]
- National Institute on Aging [P30AG 19610]
- Arizona Alzheimer's Research Consortium
- Arizona Biomedical Research Commission [4001, 0011, 05-901]
- Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson's Research
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Activated microglia appear to selectively attack dopamine (DA) neurons in the Parkinson's disease (PD) substantia nigra. We investigated potential mechanisms using culture models. As targets, human SH-SY5Y cells were left undifferentiated (UNDIFF) or were differentiated with retinoic acid (RA) or RA plus brain-derived neurotrophic factor (RA/BDNF). RA/BDNF-treated cells were immunoreactive for tyrosine hydroxylase and the DA transporter, took up exogenous DA, and released DA after K+ stimulation. Undifferentiated and RA-treated cells lacked these characteristics of a DA phenotype. Co-culture of target cells with human elderly microglia resulted in elevated toxicity in DA phenotype (RA/BDNF) cells. Lipopolysaccharide (LPS) plus K+-stimulated DA release enhanced toxicity by 500-fold. DA induced microglial chemotaxis in Boyden chambers. Spiperone inhibited this effect. Cultured human elderly microglia expressed mRNAs for D1-D4 but not D5 DA receptors. The microglia, as well as PD microglia in situ, were also immunoreactive for D1-D4 but not D5 DA receptors. These findings demonstrate that activated microglia express DA receptors, and suggest that this mechanism may play a role in the selective vulnerability of DA neurons in PD. (C) 2008 Elsevier Inc. All rights reserved.
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