Mastroeni Diego, Grover Andrew, Leonard Brian, Joyce Jeffrey N, Coleman Paul D, Kozik Brooke, Bellinger Denise L, Rogers Joseph
Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85372, United States.
Neurobiol Aging. 2009 Nov;30(11):1805-17. doi: 10.1016/j.neurobiolaging.2008.01.001. Epub 2008 Mar 5.
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.
活化的小胶质细胞似乎会选择性攻击帕金森病（PD）黑质中的多巴胺（DA）神经元。我们使用培养模型研究了潜在机制。作为靶细胞，人SH-SY5Y细胞保持未分化状态（UNDIFF），或用视黄酸（RA）或RA加脑源性神经营养因子（RA/BDNF）进行分化。经RA/BDNF处理的细胞对酪氨酸羟化酶和DA转运体呈免疫反应性，摄取外源性DA，并在K(+)刺激后释放DA。未分化和经RA处理的细胞缺乏DA表型的这些特征。靶细胞与人老年小胶质细胞共培养导致DA表型（RA/BDNF）细胞的毒性升高。脂多糖（LPS）加K(+)刺激的DA释放使毒性增强了500倍。DA在博伊登小室中诱导小胶质细胞趋化。螺哌隆抑制了这种效应。培养的人老年小胶质细胞表达D1-D4的mRNA，但不表达D5 DA受体。小胶质细胞以及原位的PD小胶质细胞对D1-D4 DA受体也呈免疫反应性，但对D5 DA受体无反应。这些发现表明活化的小胶质细胞表达DA受体，并提示该机制可能在PD中DA神经元的选择性易损性中起作用。
