Apolipoprotein D alters the early transcriptional response to oxidative stress in the adult cerebellum

Abstract

1These authors contributed equally to this study.Abbreviations used: ApoD, Apolipoprotein D; FC, fold change; FDR, false discovery rate; GC, GeneChip; GO, gene ontology; hApoD, human ApoD; KO, knock-out; NS, nervous system; OS, oxidative stress; Pkcd, Protein kinase Cd; PQ, paraquat; RMA, robust multiarray average algorithm; RS, reactive species; Tg, transgenic; WT, wild-type. AbstractThe lipocalin Apolipoprotein D (ApoD), known to protect the nervous system against oxidative stress (OS) in model organisms, is up-regulated early in the mouse brain in response to the ROS generator paraquat. However, the processes triggered by this up-regulation have not been explored. We present here a study of the effect of ApoD on the early transcriptional changes upon OS in the mouse cerebellum using microarray profiling. ApoD-KO and transgenic mice over-expressing ApoD in neurons are compared to wild-type controls. In control conditions, ApoD affects the transcriptional profile of neuron and oligodendrocyte-specific genes involved in neuronal excitability, synaptic function, and myelin homeostasis. When challenged with paraquat, the absence of ApoD modifies the response of genes mainly related to OS management and myelination. Interestingly, the over-expression of ApoD in neurons almost completely abolishes the early transcriptional response to OS. We independently evaluate the expression of protein kinase Cd, a gene up-regulated by OS only in the ApoD-KO cerebellum, and find it overexpressed in cultured ApoD-KO primary astrocytes, which points to a role for ApoD in astrocyte-microglia signaling. Our results support the hypothesis that ApoD is necessary for a proper response of the nervous system against physiological and pathological OS.

Grasshopper Lazarillo, a GPI-anchored Lipocalin, increases Drosophila longevity and stress resistance, and functionally replaces its secreted homolog NLaz

“…7C). As it has been described for the vertebrate homologue ApoD in the mouse (Bajo-Graneras et al, 2011a, 2011bGanfornina et al, 2008;Ganfornina et al 2010), without additional stress the absence of NLaz might cause an imbalance in tissue homeostasis, generating a basal level of stress. This in turn might cause the observed slight GLaz up-regulation.…”

Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems

“…Recently, we have found that acute high doses of PQ induce ApoD-dependent oligodendrocyte gene expression responses in the cerebellum (Bajo-Grañeras et al, 2011). In contrast, no genotype-dependent differential expression of myelin genes was seen in the SN in response to chronic PQ (not shown), indicating that this experimental paradigm is able to trigger a specific astroglial response to oxidative damage, with minor contribution of microglial or oligodendrocyte responses.…”

“…9E). This up-regulation of GFAP protein could be controlled at transcriptional levels, since the lack of ApoD up-regulates Nf1a, a known activator of GFAP gene transcription, upon acute PQ treatment in the cerebellum (Bajo-Grañeras et al, 2011).…”

“…We focused on genes that can be expressed by glial cells, since ApoD is not expressed by nigral dopaminergic neurons (Ordonez et al, 2006). Damage to neurons, and oxidative damage in general, triggers mainly astrocyte responses (Bajo-Grañeras et al, 2011;Rossi and Volterra, 2009) while inflammatory insults directly trigger microglial responses (Morale et al, 2006).…”

Expression and potential role of apolipoprotein D on the death–survival balance of human colorectal cancer cells under oxidative stress conditions

“…This effect was associated with a role in regulating tissue homeostasis and in maintaining low levels of lipid peroxidation [13][14][15]. We have recently shown that ApoD contributes to reduce inflammation levels in ROS-injured tissues and promotes the clearance of lipid peroxides in cells [16,17].…”