Apolipoprotein D (ApoD), a lipocalin transporter of small hydrophobic molecules, plays an essential role in several neurodegenerative diseases. It was reported that increased immunostaining for ApoD of glial cells surrounding dopaminergic (DAergic) neurons was observed in the brains of Parkinson’s disease (PD) patients. Although preliminary findings supported the role of ApoD in neuroprotection, its derivation and effects on the degeneration of nigral DAergic neurons are largely unknown. In the present study, we observed that ApoD levels released from astrocytes were increased in PD models both in vivo and in vitro. When co-cultured with astrocytes, due to the increased release of astrocytic ApoD, the survival rate of primary cultured ventral midbrain (VM) neurons was significantly increased with 1-methyl-4-phenylpyridillium ion (MPP⁺) treatment. Increased levels of TAp73 and its phosphorylation at Tyr99 in astrocytes were required for the increased ApoD levels and its release. Conditional knockdown of TAp73 in the nigral astrocytes in vivo could aggravate the neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mice. Our findings reported that astrocyte-derived ApoD was essential for DAergic neuronal survival in PD models, might provide new therapeutic targets for PD.

载脂蛋白 D (ApoD) 是一种疏水性小分子的脂质运载蛋白转运蛋白，在多种神经退行性疾病中发挥着重要作用。据报道，在帕金森病 (PD) 患者的大脑中观察到多巴胺能 (DAergic) 神经元周围的胶质细胞 ApoD 免疫染色增加。尽管初步研究结果支持 ApoD 在神经保护中的作用，但其来源和对黑质 DAergic 神经元变性的影响在很大程度上尚不清楚。在本研究中，我们观察到在体内和体外的 PD 模型中，星形胶质细胞释放的 ApoD 水平均有所增加。当与星形胶质细胞共培养时，由于星形胶质细胞ApoD的释放增加，原代培养的腹侧中脑（VM）神经元的存活率在1-甲基-4-苯基吡啶鎓离子（MPP ⁺ ）处理下显着增加。星形胶质细胞中 TAp73 水平及其 Tyr99 磷酸化水平的增加是 ApoD 水平增加及其释放所必需的。体内黑质星形胶质细胞中TAp73的条件性敲低可能会加剧1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）治疗的PD小鼠的神经变性。我们的研究结果表明，星形胶质细胞衍生的 ApoD 对于 PD 模型中 DAergic 神经元的存活至关重要，可能为 PD 提供新的治疗靶点。