Astrocyte-derived apolipoprotein D is required for neuronal survival in Parkinson’s disease

Apolipoprotein D (Apo D), a lipocalin transporter of small hydrophobic molecules, plays an important role in several neurodegenerative diseases. It was reported that increased immunostaining for Apo D of glial cells surrounding dopmainergic (DAergic) neurons was observed in the brains of Parkinson’s disease (PD) patients. Although preliminary findings supported the role of Apo D in neuroprotection, its derivation and effects on the degeneration of nigral DAergic neurons are largely unknown. In the present study, we observed that Apo D levels released from astrocytes were increased in PD both in vivo and in vitro . When co-cultured with astrocytes, due to the increased release of astrocytic Apo D, 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 Apo D 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, for the first time, astrocyte-derived Apo D was essential for DAergic neuronal survival in PD, which might provide new therapeutic targets for PD.