Apolipoprotein D (ApoD) is a member of the lipocalin family associated with the high density lipoproteins. ApoD binds lipophylic molecules and is secreted in many vertebrate tissues, where is expressed in response to many pathological conditions. We are interested in the nervous system because ApoD increases its expression during aging, oxidative-stress conditions and in neurological disorders, including Ataxia and Alzheimer's disease.ApoD has a neuroprotector role in animal models subjected to oxidative stress induced by paraquat (PQ). This substance triggers cell death by reactive oxygen species (ROS) generation.

Using a human astrocytic cell line (1321N1) exposed to PQ, we aim at typifying the ApoD molecular mechanism of action. PQ treatment increases ApoD expression when cells initiate apoptosis. Our goal is to understand how ApoD is regulated by the signaling cascades triggered by oxidative and inflammatory stimuli, and how its expression intervenes in the control of the proliferation-death balance.One of the signaling networks activated by the same stimulus that induce ApoD expression is controlled by MAP kinases. We are using specific inhibitors in order to block the activation of p38, MEK and JNK, to study the changes in ApoD protein expression. We have chosen these inhibitors because recognition sequences for transcription factors of this cascade have been described in the ApoD promoter. By now, our data suggest that the PQ dependent ApoD expression is inhibited when JNK is blocked, indicating that ApoD is up-regulated by this apoptotic pathway. This work was supported by MEC grant BFU2005-00522, and JCyL grant VA049A05 to M.D.G. and D.S.