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. Author manuscript; available in PMC: 2013 Jun 24.
Published in final edited form as: Cell Cycle. 2010 Jan 26;9(2):269–273. doi: 10.4161/cc.9.2.10433

Apolipoprotein D

An overview of its role in aging and age-related diseases

Julien Muffat 1,, David W Walker 2,3,*
PMCID: PMC3691099  NIHMSID: NIHMS466507  PMID: 20023409

Abstract

It’s got to be doing something important!

—Seymour Benzer, reflecting on the observation that ApoD mRNA levels increase 500-fold following neuronal crush injury.

Seymour Benzer’s curiosity was legendary and seemingly limitless.1-5 Towards the end of his life, one of the (many) questions that kept him awake at night concerned the emerging role of Apolipoprotein D (ApoD) in aging and neurological disease. In this perspective, we will discuss the clinical and biochemical data on ApoD, and the input from the recent genetic studies in model systems, including those from the Benzer lab.

Keywords: ApoD, GLaz, NLaz, drosophila, aging, p53, cancer

Molecular Biology of Apolipoprotein D (ApoD)

Apolipoprotein D (ApoD) is a secreted glycoprotein assigned with many putative functions including lipid transport. Human ApoD was first formally identified in plasma High Density Lipopoproteins (HDL) in 1973.6 The cDNA is 855 bp long,7 processed from a gene region with 5 exons spanning 20 kbp, typical of the superfamily.8 In silico promoter analysis identified multiple steroid response elements (RE) upstream of the ApoD gene.9 Further analysis in cell culture showed the gene was also under the primary control of serum-responsive elements during cellular growth arrest, and has response elements for oestrogen, glucocorticoids, progesterone, and vitamins A and D.10

In humans, the protein is widely expressed, unlike other apolipoproteins, which are mainly produced by the liver, hinting at fundamental cellular functions.11 However, its main sites of expressions are the brain and the testes. In the central nervous system, it is mainly expressed in glial cells (both astrocytes and oligodendrocytes) and their precursors,12 but can also be expressed by neurons in pathological situations. The protein itself is predicted to be small (18 kD), soluble and secreted and has no homology to other apolipoproteins (such as the well-known ApoE).11 Early studies showed diverse levels of glycosylation, sometimes specific to expression site.11 Based on its primary sequence, it was predicted to be a member of the lipocalin family of proteins. These are cup-shaped molecules, presenting 8 beta-pleated sheets arranged in a calyx structure, capable of binding a single hydrophobic ligand in the pocket they form. This was recently confirmed by the 1.8A structure of a hydrophilized form of recombinant ApoD.13,14 These studies highlighted the presence of hydrophobic residues outside of the binding pocket, which may allow the molecule to interact with membranes or HDL, and favor ligand exchange, while the base of the calyx could provide a docking site for an unidentified cellular receptor. Both the crystallization studies and earlier affinity assays, point to arachidonic acid (AA) and progesterone (PG) as putative physiological ligands for ApoD.15,16

A complicated picture of ApoD biology has emerged from these biochemical studies. The protein is expressed in many different tissues, with different glycosylation profiles. It can bind with micromolar affinity several ligands, and interact with membranes and circulating lipid particles and its expression appears to be under the control of a complex array of regulatory elements. ApoD is potentially a protein with multiple ligands and interacting partners, through which it can exert multiple different functions in different tissues.

ApoD and Neurological Disorders and Nerve Injury

ApoD has been described in association with various neurological disorders, including Alzheimer’s Disease (AD), Parkinson’s disease (PD) and stroke.11 Interestingly, oxidative stress has been implicated in the etiology of each of these pathologies.17,18 For example, an imbalance in reactive oxygen species (ROS) production and clearance in the dopaminergic neurons of the substantia nigra (SN) has long been linked to neuronal cell death in PD. Recently, it was reported that high levels of ApoD could be found in the SN of patients with PD.19 In this case, the neurons that are the target of the pathology do not express ApoD, but the surrounding glial cells display an increased immuno-reactivity. ApoD has also been found to be elevated in the brains of patients with Alzheimer’s disease (two-fold elevation over age-matched controls).20,21 In these patients, expression can be seen in oligodendrocytes and astrocytes, but also in neurons affected by neurofibrillary tangles, and in the vicinity of amyloid plaques. It is also worth noting that a particular allele of ApoD was enriched in AD patients, in a small African American sample,22,23 while another allele was enriched in a Finnish population with early onset AD.24

Since ApoD is a lipid carrier, it is particularly interesting to observe its upregulation in disorders of the myelin sheath. Cerebrospinal fluid levels and plasma ApoD levels are significantly elevated in multiple sclerosis and other inflammatory diseases of the central nervous system.25 As mentioned in our introduction, one of the most striking increases is observed in regenerating and remyelinating sciatic nerve, in the rat. After 3 weeks post-crush injury, ApoD increases 500-fold at the site of the lesion, and remains elevated while attempts at regeneration take course.26

More recently, in a rat model of stroke, ApoD was found to increase up to a week after reperfusion, in the penumbra of the injury.27,28 It is important to note that ApoD protein levels, but not its mRNA, increased in the dying neurons. On the contrary, in the zone bordering the infarct, oligodendrocytes were shown to upregulate ApoD mRNA expression, thereby suggesting secretion and recruitment in the dying areas.

ApoD and Psychiatric Disorders

ApoD has also been associated with psychiatric disorders such as Schizophrenia and bipolar disorder.29 For example, circulating ApoD is elevated in the serum of schizophrenic patients receiving no medication, and in the brains of treated patients.30,31 Similarly, a two-fold increase in ApoD can be found in the prefrontal cortex of patients with either schizophrenia or bipolar disorder, but a concurrent two-fold increase in the parietal cortex appears to be specific of bipolar disorder patients.32 It is possible that ApoD’s elevation in these specific regions is related to the membrane pathology observed in these disorders. It is therefore interesting to find that high ApoD levels correlate with membrane AA in schizophrenic patients’ erythrocytes.33

Interestingly, antipsychotic drugs that work best in treating these psychiatric disorders—atypical antipsychotics such as clozapine—further elevate the levels of ApoD.34 One may therefore suggest that ApoD elevation in these disorders, and a further boost by drugs, can act to prevent deleterious events, stabilizing membrane bound AA.

ApoD, Cancer and the p53 Family

In recent years, a number of studies have reported alterations in ApoD expression in relation to cancer.35-37 In general, ApoD expression correlates inversely with aggressive behavior of several different types of malignant tumors. Although the underlying mechanism has not yet been elucidated, ApoD has been shown to function in cell growth inhibition.38-41 Recently, it was reported that ApoD is a direct transcriptional target of p53 family members p73 and p63.42 p53 is probably the best-studied tumor suppressor gene, and is found to be mutated or inactive in up to 70% of all cancers. p53 protein is present at low levels in normal cells but is activated in response to a variety of environmental stimuli, including DNA damage, hypoxia, viral infection, or oncogene activation, resulting in transactivation of a specific set of target genes. These targets are involved in cell cycle control, apoptosis, DNA replication, repair, proliferation, inhibition of angiogenesis, and cellular stress response.43 Both p73 and p63, share high homology to p53, especially in the central DNA binding domain. Therefore, these p53 family members may overlap functionally with p53. Interestingly, in the same study it was reported that addition of recombinant human ApoD to culture medium was associated with an inhibition of cancer cell proliferation in vitro.

Age-Related Changes in ApoD Expression

Aging is the greatest risk factor for most cancers and neurological disorders. However, the underlying molecular mechanisms relevant to the aging process remain poorly understood. Many microarray studies have been conducted in several species, including humans, to gain insights into the aging process.44 A recent study performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats and humans.45 The objective of the study was to identify genes with the largest number of putatively age-related signals in multiple datasets. The study identified 56 genes that were consistently upregulated as a function of age, with ApoD being identified as the most significant. An independent study set out to compare age-related changes in gene expression in the cortex of humans, rhesus macaques and mice.46 A major conclusion of the comparison of all three species was that the most robustly age-upregulated gene was ApoD.

These reports clearly identify ApoD as a “suspect at many different crime scenes,” including the aging brain. The question is whether ApoD is the perpetrator, an innocent bystander or a ‘good Samaritan’ trying to help the ‘victim’ under attack.

Modeling the Role of ApoD Homologs in Longevity and Stress Resistance

Our own interest in ApoD began when we performed a genetic screen to identify genes that protect the fruit fly Drosophila against oxygen stress. As is often the case, there were a relatively large number (~20) of “hits” from the screen. One of these “hits,” Glial Lazarillo (GLaz), was a fly homolog of human ApoD. After exposing flies to a sub-lethal dose of oxygen stress, we remember showing our mentor, Seymour Benzer, the very active flies that were overexpressing GLaz next to the very sickly control flies. From that day on, we would discuss ApoD on an almost daily basis until the end of Seymour’s life.

To validate the protective effects of Glaz, we generated independent transgenic lines carrying the GLaz cDNA under control of the UAS/GAL4 system.47 Upon doing so, we discovered that overexpression of Glaz protected against a range of extrinsic stressors and extended the lifespan of normal flies by ~30%.48 An independent loss-of-function study revealed that GLaz mutants are sensitive to both oxidative and starvation stress.49 Interestingly, a GLaz-GFP reporter line was expressed in glial cells in the adult fly brain. This expression pattern is consistent with the developmental expression pattern of GLaz in Drosophila,50 and with the mainly glial expression pattern of vertebrate ApoD.51-53 In addition, GLaz gene activity was found to protect against neuronal apoptosis as a function of both age and extrinsic oxidative stress.49 At a physiological level, GLaz mutant flies display decreased fat content,49 highlighting a putative role for GLaz in lipid metabolism.

As well as GLaz, the Drosophila genome contains another lipocalin gene: Neural Lazarillo (NLaz), which is expressed in a subset of neuronal cells, and, interestingly, in the developing fat body.50 Recently, it was reported that NLaz plays an important role in regulating metabolic homeostasis and longevity in the fly.54 Activation of the Jun-N-terminal Kinase (JNK) signaling pathway, which can be induced by a variety of environmental stressors, including oxidative stress, represses insulin/IGF-1 signaling (IIS) activity, extending lifespan but limiting growth.55,56 In a candidate gene approach, NLaz was identified as a downstream transcriptional target of JNK signaling.54 Moreover, NLaz mutant flies were found to display reduced stores and rapid starvation-induced decline of glucose, trehalose, glycogen and triglyceride levels and were sensitive to starvation. In contrast, overexpression of NLaz in the fat-body was found to increase starvation resistance, suggesting that JNK-mediated induction of NLaz in the fatbody regulates metabolic homeostasis. In support of this idea, fatbody expression of NLaz is sufficient to restore starvation resistance in flies mutant for the JNK activating Kinase Hemipterous (JNKK/Hep).

In the same study, it was reported that loss of NLaz confers sensitivity to both dietary paraquat and hyperoxia while overexpression of NLaz both ubiquitously and in the fatbody, protects against oxidative stress.54 Finally and importantly, the role of NLaz in modulating longevity was also examined. Consistent with the GLaz findings,48,49 NLaz mutant flies are short-lived relative to isogenic controls, while overexpression of NLaz with a ubiquitous driver increases fly lifespan.

These findings are intriguing and provocative: manipulating the expression of either Glaz or Nlaz results in changes in resistance to extrinsic stress and longevity. However, there appear to be important differences in the regulation of the two fly lipocalins. While NLaz expression is controlled by JNK signaling, GLaz expression is not.54

Recently, two additional studies have reported characterizing the function of ApoD homologs in mammals57 and also in plants.58 An ApoD knockout mouse (ApoD-KO) was generated by replacing the wild-type ApoD gene with a copy interrupted by the insertion of the neomycin resistance gene, which rendered a transcription null mutant. Interestingly, ApoD-KO mice display reduced locomoter and exploratory behavior as well as deficits in learning.57 Remarkably, murine ApoD appears to protect against oxidative stress also. ApoD null mice display reduced tolerance to the ROS generator paraquat. This result was observed in two different genetic backgrounds, strongly indicating that loss of ApoD gene function is responsible for the phenotype. Bioinformatic studies have revealed that plants also possess lipocalins, which were classified as temperature-induced lipocalins (TILs), including the ApoD ortholog AtTIL identified in Arabidopsis thaliana.59 AtTIL knock-out plants are acutely sensitive to oxidative stress, cold and light.58 Whereas, overexpression of the normal gene confers resistance to extrinsic stress.

The upregulation of human ApoD (hApoD) in various diseases involving chronic stress, predicts that experimentally induced stress may regulate the expression of ApoD orthologs in model systems. To gain insight into this question, we examined the regulation of GLaz as a function of extrinsic stress. Quantitative real-time PCR (qRT-PCR) revealed that GLaz mRNA levels were dramatically increased in response to dietary paraquat, hyperoxia or heat stress.60 In addition, NLaz expression is also induced in response to both oxidative stress and starvation stress.54 A careful study in mice has revealed the temporal and spatial expression of ApoD in response to oxidative stress.57 An acute upregulation of ApoD in mouse brain was observed 3 hours after exposure to paraquat, and the expression returns to baseline by 24 hours. No upregulation was observed in the lung or liver. In plants, AtTIL is induced by both thermal and water stress.61

Understanding the relationship between different stressors and ApoD induction may shed light on the mechanisms underlying neurological disease. Towards this goal, a recent study examined the response of ApoD to a range of stressors in cell culture.62 Interestingly, stresses that cause an extended growth arrest, such as UV light or hydrogen peroxide, increase ApoD expression. This study also addressed the subcellular localization of ApoD under normal and stressful conditions. Interestingly, under normal conditions ApoD is mainly perinuclear but it accumulates in the cytoplasm and nucleus under stressful conditions. In fact, exogenous ApoD from the medium can be taken up by cells and translocated in this way, making the search for the receptor(s) involved in this trafficking a high priority in ApoD research. These studies in plants, insects and mammals strongly support a conserved function for these lipocalins, responding to and protecting against extrinsic and intrinsic stress.

Manipulating Human ApoD (hApoD) Gene Activity

As outlined above, ApoD homologs in model systems appear to show conservation of both regulation and function. But what about the human gene itself? To examine the role of human ApoD (hApoD) on longevity and stress resistance directly, we generated two independent transgenic fly lines carrying the hApoD cDNA under control of the UAS/GAL4 system.47 Using this system, we have shown that overexpression of hApoD in flies protects against oxidative stress and extends lifespan under normal conditions.60 To examine the role of hApoD in mice, a transgenic animal (HApoD-Tg) overexpressing hApoD under the control of a neuronal promoter was generated.57 Indeed, HApoD-Tg mice display improved survival following exposure to two different concentrations of paraquat. In addition, Do Carmo et al. showed conclusively that ApoD overexpression is sufficient to temper inflammation observed in coronavirus-induced encephalitis.63 The study of mutant mice in similar conditions would also greatly inform our current understanding of some of ApoD’s physiological functions.

The insulin/IGF signaling (IIS) pathway modulates lifespan in several species ranging from yeast to mammals, and thus appears to be evolutionarily conserved.64 Recently, it was reported that neuronal expression of hApoD in mice results in alterations in glucose and insulin metabolism. More precisely, although they are not obese and have normal lipid concentration in circulation, hApoD mice are glucose intolerant, insulin resistant, and develop hepatic steatosis.65 These findings suggest that the interaction between IIS-mediated longevity and ApoD-mediated longevity warrants more attention.

Closing Remarks

ApoD is emerging as a focal point in a number of studies investigating the molecular basis of aging and age-related diseases. For the most part, these studies have been correlative in nature. However, a number of recent genetic studies in flies, mice and plants have demonstrated that manipulating ApoD gene activity can have profound physiological consequences. These studies, whether using ApoD homologs or human ApoD transgenics, have greatly advanced the field: we now know that ApoD can act as a “good Samaritan” helping cells and organisms better cope with both extrinsic and intrinsic stress. We note that whether we consider cancers or neuronal disorders, there is an underlying age-dependency. Therefore, it seems particularly important that both GLaz and NLaz modulate lifespan in flies. In part, the involvement of ApoD in age-related disorders could be related to a direct scavenging activity against free radical damage. Studies in both mice and flies have shown ApoD’s ability to decrease lipid peroxides in membranes.57,60 Future work should focus on establishing exactly how ApoD decreases lipoxic damage in aging animals.

Over the years, ApoD has been studied from widely different angles, which are today primed to coalesce, and provide a significant new understanding of its various roles. However, the community working on this protein and its homologs has only started to scratch the surface of ApoD’s mechanisms of action. The recent elucidation of its crystal structure can only benefit biochemical studies of ligands and interacting partners, and provide educated targets for mutational analysis. If direct ligand interactions are involved in these therapeutic approaches, it is important to note that ApoD will benefit from work to generate anticalins, engineered lipocalins, with customized affinities for lipidic ligands of choice.66

Taken together, the studies described in this perspective strongly suggest that ApoD may provide an important therapeutic target for several devastating diseases. In characteristic fashion, Seymour Benzer’s contribution to this emerging field was both timely and important. Seymour’s overwhelming excitement and enthusiasm for the ApoD projects, both in his own lab and in the labs of his colleagues, was both inspiring and contagious. For this, and all the lessons in science and life that we picked up sitting around the table in the Benzer lunchroom we are deeply grateful.

Acknowledgments

We dedicate this perspective to our mentor Seymour Benzer. D.W.W. is funded by the American Federation for Aging Research to study the mechanisms of ApoD-mediated longevity in flies. D.W.W. received support from the UCLA Older Americans Independence Center, NIH/NIA Grant P30-AG028748 and the content does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. D.W.W. also received support from the Ellison Medical Foundation and the UCLA Center for gene environment in Parkinson’s Disease. D.W.W. is an Ellison Medical Foundation New Scholar in Aging.

References

  • 1.Anderson D, Brenner S. Obituary: Seymour Benzer (1921–2007) Nature. 2008;451:139. doi: 10.1038/451139a. [DOI] [PubMed] [Google Scholar]
  • 2.Dudai Y. Seymour Benzer (1921–2007) Neuron. 2008;57:24–6. doi: 10.1016/j.neuron.2007.12.014. [DOI] [PubMed] [Google Scholar]
  • 3.Greenspan RJ. Seymour Benzer (1921–2007) Curr Biol. 2008;18:106–10. doi: 10.1016/j.cub.2007.12.039. [DOI] [PubMed] [Google Scholar]
  • 4.Jan YN, Jan L. Retrospective: Seymour Benzer (1921–2007) Science. 2008;319:45. doi: 10.1126/science.1154050. [DOI] [PubMed] [Google Scholar]
  • 5.Tanouye MA. Seymour Benzer 1921–2007. Nat Genet. 2008;40:121. doi: 10.1038/ng0208-121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.McConathy WJ, Alaupovic P. Isolation and partial characterization of apolipoprotein D: a new protein moiety of the human plasma lipoprotein system. FEBS Lett. 1973;37:178–82. doi: 10.1016/0014-5793(73)80453-3. [DOI] [PubMed] [Google Scholar]
  • 7.Drayna D, Fielding C, McLean J, Baer B, Castro G, Chen E, et al. Cloning and expression of human apolipoprotein D cDNA. J Biol Chem. 1986;261:16535–9. [PubMed] [Google Scholar]
  • 8.Sanchez D, Ganfornina MD, Gutierrez G, Marin A. Exon-intron structure and evolution of the Lipocalin gene family. Mol Biol Evol. 2003;20:775–83. doi: 10.1093/molbev/msg079. [DOI] [PubMed] [Google Scholar]
  • 9.Lambert J, Provost PR, Marcel YL, Rassart E. Structure of the human apolipoprotein D gene promoter region. Biochim Biophys Acta. 1993;1172:190–2. doi: 10.1016/0167-4781(93)90292-l. [DOI] [PubMed] [Google Scholar]
  • 10.Do Carmo S, Seguin D, Milne R, Rassart E. Modulation of apolipoprotein D and apolipoprotein E mRNA expression by growth arrest and identification of key elements in the promoter. J Biol Chem. 2002;277:5514–23. doi: 10.1074/jbc.M105057200. [DOI] [PubMed] [Google Scholar]
  • 11.Rassart E, Bedirian A, Do Carmo S, Guinard O, Sirois J, Terrisse L, et al. Apolipoprotein D. Biochim Biophys Acta. 2000;1482:185–98. doi: 10.1016/s0167-4838(00)00162-x. [DOI] [PubMed] [Google Scholar]
  • 12.Hu CY, Ong WY, Sundaram RK, Chan C, Patel SC. Immunocytochemical localization of apolipoprotein D in oligodendrocyte precursor-like cells, perivascular cells, and pericytes in the human cerebral cortex. J Neurocytol. 2001;30:209–18. doi: 10.1023/a:1012797623620. [DOI] [PubMed] [Google Scholar]
  • 13.Eichinger A, Nasreen A, Kim HJ, Skerra A. Structural insight into the dual ligand specificity and mode of high density lipoprotein association of apolipoprotein D. J Biol Chem. 2007;282:31068–75. doi: 10.1074/jbc.M703552200. [DOI] [PubMed] [Google Scholar]
  • 14.Nasreen A, Vogt M, Kim HJ, Eichinger A, Skerra A. Solubility engineering and crystallization of human apolipoprotein D. Protein Sci. 2006;15:190–9. doi: 10.1110/ps.051775606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Morais Cabral JH, Atkins GL, Sanchez LM, Lopez-Boado YS, Lopez-Otin C, Sawyer L. Arachidonic acid binds to apolipoprotein D: implications for the protein’s function. FEBS Lett. 1995;366:53–6. doi: 10.1016/0014-5793(95)00484-q. [DOI] [PubMed] [Google Scholar]
  • 16.Vogt M, Skerra A. Bacterially produced apolipoprotein D binds progesterone and arachidonic acid, but not bilirubin or E-3M2H. J Mol Recognit. 2001;14:79–86. doi: 10.1002/1099-1352(200101/02)14:1<79::AID-JMR521>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
  • 17.Andersen JK. Oxidative stress in neurodegeneration: cause or consequence? Nat Med. 2004;10:18–25. doi: 10.1038/nrn1434. [DOI] [PubMed] [Google Scholar]
  • 18.Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359–407. doi: 10.1146/annurev.genet.39.110304.095751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ordonez C, Navarro A, Perez C, Astudillo A, Martinez E, Tolivia J. Apolipoprotein D expression in substantia nigra of Parkinson disease. Histol Histopathol. 2006;21:361–6. doi: 10.14670/HH-21.361. [DOI] [PubMed] [Google Scholar]
  • 20.Kalman J, McConathy W, Araoz C, Kasa P, Lacko AG. Apolipoprotein D in the aging brain and in Alzheimer’s dementia. Neurol Res. 2000;22:330–6. doi: 10.1080/01616412.2000.11740678. [DOI] [PubMed] [Google Scholar]
  • 21.Terrisse L, Poirier J, Bertrand P, Merched A, Visvikis S, Siest G, et al. Increased levels of apolipoprotein D in cerebrospinal fluid and hippocampus of Alzheimer’s patients. J Neurochem. 1998;71:1643–50. doi: 10.1046/j.1471-4159.1998.71041643.x. [DOI] [PubMed] [Google Scholar]
  • 22.Desai PP, Hendrie HC, Evans RM, Murrell JR, DeKosky ST, Kamboh MI. Genetic variation in apolipoprotein D affects the risk of Alzheimer disease in African-Americans. Am J Med Genet B Neuropsychiatr Genet. 2003;116:98–101. doi: 10.1002/ajmg.b.10798. [DOI] [PubMed] [Google Scholar]
  • 23.Desai PP, Bunker CH, Ukoli FA, Kamboh MI. Genetic variation in the apolipoprotein D gene among African blacks and its significance in lipid metabolism. Atherosclerosis. 2002;163:329–38. doi: 10.1016/s0021-9150(02)00012-6. [DOI] [PubMed] [Google Scholar]
  • 24.Helisalmi S, Hiltunen M, Vepsalainen S, Iivonen S, Corder EH, Lehtovirta M, et al. Genetic variation in apolipoprotein D and Alzheimer’s disease. J Neurol. 2004;251:951–7. doi: 10.1007/s00415-004-0470-8. [DOI] [PubMed] [Google Scholar]
  • 25.Reindl M, Knipping G, Wicher I, Dilitz E, Egg R, Deisenhammer F, et al. Increased intrathecal production of apolipoprotein D in multiple sclerosis. J Neuroimmunol. 2001;119:327–32. doi: 10.1016/s0165-5728(01)00378-2. [DOI] [PubMed] [Google Scholar]
  • 26.Boyles JK, Notterpek LM, Anderson LJ. Accumulation of apolipoproteins in the regenerating and remyelinating mammalian peripheral nerve. Identification of apolipoprotein D, apolipoprotein A-IV, apolipoprotein E and apolipoprotein A-I. J Biol Chem. 1990;265:17805–15. [PubMed] [Google Scholar]
  • 27.Rickhag M, Deierborg T, Patel S, Ruscher K, Wieloch T. Apolipoprotein D is elevated in oligodendrocytes in the peri-infarct region after experimental stroke: influence of enriched environment. J Cereb Blood Flow Metab. 2008;28:551–62. doi: 10.1038/sj.jcbfm.9600552. [DOI] [PubMed] [Google Scholar]
  • 28.Rickhag M, Wieloch T, Gido G, Elmer E, Krogh M, Murray J, et al. Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia-induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue. J Neurochem. 2006;96:14–29. doi: 10.1111/j.1471-4159.2005.03508.x. [DOI] [PubMed] [Google Scholar]
  • 29.Thomas EA, Copolov DL, Sutcliffe JG. From pharmacotherapy to pathophysiology: emerging mechanisms of apolipoprotein D in psychiatric disorders. Curr Mol Med. 2003;3:408–18. doi: 10.2174/1566524033479681. [DOI] [PubMed] [Google Scholar]
  • 30.Thomas EA, Dean B, Pavey G, Sutcliffe JG. Increased CNS levels of apolipoprotein D in schizophrenic and bipolar subjects: implications for the pathophysiology of psychiatric disorders. Proc Natl Acad Sci USA. 2001;98:4066–71. doi: 10.1073/pnas.071056198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Mahadik SP, Khan MM, Evans DR, Parikh VV. Elevated plasma level of apolipoprotein D in schizophrenia and its treatment and outcome. Schizophr Res. 2002;58:55–62. doi: 10.1016/s0920-9964(01)00378-4. [DOI] [PubMed] [Google Scholar]
  • 32.Thomas EA, Dean B, Scarr E, Copolov D, Sutcliffe JG. Differences in neuroanatomical sites of apoD elevation discriminate between schizophrenia and bipolar disorder. Mol Psychiatry. 2003;8:167–75. doi: 10.1038/sj.mp.4001223. [DOI] [PubMed] [Google Scholar]
  • 33.Yao JK, Thomas EA, Reddy RD, Keshavan MS. Association of plasma apolipoproteins D with RBC membrane arachidonic acid levels in schizophrenia. Schizophr Res. 2005;72:259–66. doi: 10.1016/j.schres.2004.05.007. [DOI] [PubMed] [Google Scholar]
  • 34.Thomas EA, George RC, Danielson PE, Nelson PA, Warren AJ, Lo D, et al. Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins. Mol Psychiatry. 2003;8:983–93. doi: 10.1038/sj.mp.4001425. [DOI] [PubMed] [Google Scholar]
  • 35.Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C, et al. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene. 2006;25:3994–4008. doi: 10.1038/sj.onc.1209415. [DOI] [PubMed] [Google Scholar]
  • 36.Hunter S, Weiss S, Ou CY, Jaye D, Young A, Wilcox J, et al. Apolipoprotein D is downregulated during malignant transformation of neurofibromas. Hum Pathol. 2005;36:987–93. doi: 10.1016/j.humpath.2005.06.018. [DOI] [PubMed] [Google Scholar]
  • 37.Hunter SB, Varma V, Shehata B, Nolen JD, Cohen C, Olson JJ, et al. Apolipoprotein D expression in primary brain tumors: analysis by quantitative RT-PCR in formalin-fixed, paraffin-embedded tissue. J Histochem Cytochem. 2005;53:963–9. doi: 10.1369/jhc.4A6530.2005. [DOI] [PubMed] [Google Scholar]
  • 38.Jin D, El-Tanani M, Campbell FC. Identification of apolipoprotein D as a novel inhibitor of osteopontin-induced neoplastic transformation. Int J Oncol. 2006;29:1591–9. [PubMed] [Google Scholar]
  • 39.Sugimoto K, Simard J, Haagensen DE, Labrie F. Inverse relationships between cell proliferation and basal or androgen-stimulated apolipoprotein D secretion in LNCaP human prostate cancer cells. J Steroid Biochem Mol Biol. 1994;51:167–74. doi: 10.1016/0960-0760(94)90090-6. [DOI] [PubMed] [Google Scholar]
  • 40.Lopez-Boado YS, Puente XS, Alvarez S, Tolivia J, Binderup L, Lopez-Otin C. Growth inhibition of human breast cancer cells by 1,25-dihydroxyvitamin D3 is accompanied by induction of apolipoprotein D expression. Cancer Res. 1997;57:4091–7. [PubMed] [Google Scholar]
  • 41.Sarjeant JM, Lawrie A, Kinnear C, Yablonsky S, Leung W, Massaeli H, et al. Apolipoprotein D inhibits platelet-derived growth factor-BB-induced vascular smooth muscle cell proliferated by preventing translocation of phosphorylated extracellular signal regulated kinase 1/2 to the nucleus. Arterioscler Thromb Vasc Biol. 2003;23:2172–7. doi: 10.1161/01.ATV.0000100404.05459.39. [DOI] [PubMed] [Google Scholar]
  • 42.Sasaki Y, Negishi H, Koyama R, Anbo N, Ohori K, Idogawa M, et al. p53 family members regulate the expression of the apolipoprotein D gene. J Biol Chem. 2009;284:872–83. doi: 10.1074/jbc.M807185200. [DOI] [PubMed] [Google Scholar]
  • 43.Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–10. doi: 10.1038/35042675. [DOI] [PubMed] [Google Scholar]
  • 44.Zahn JM, Kim SK. Systems biology of aging in four species. Curr Opin Biotechnol. 2007;18:355–9. doi: 10.1016/j.copbio.2007.07.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.de Magalhaes JP, Curado J, Church GM. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics. 2009;25:875–81. doi: 10.1093/bioinformatics/btp073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Loerch PM, Lu T, Dakin KA, Vann JM, Isaacs A, Geula C, et al. Evolution of the aging brain tran-scriptome and synaptic regulation. PLoS One. 2008;3:3329. doi: 10.1371/journal.pone.0003329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993;118:401–15. doi: 10.1242/dev.118.2.401. [DOI] [PubMed] [Google Scholar]
  • 48.Walker DW, Muffat J, Rundel C, Benzer S. Overexpression of a Drosophila homolog of apolipoprotein D leads to increased stress resistance and extended lifespan. Curr Biol. 2006;16:674–9. doi: 10.1016/j.cub.2006.01.057. [DOI] [PubMed] [Google Scholar]
  • 49.Sanchez D, Lopez-Arias B, Torroja L, Canal I, Wang X, Bastiani MJ, et al. Loss of glial lazarillo, a homolog of apolipoprotein D, reduces lifespan and stress resistance in Drosophila. Curr Biol. 2006;16:680–6. doi: 10.1016/j.cub.2006.03.024. [DOI] [PubMed] [Google Scholar]
  • 50.Sanchez D, Ganfornina MD, Torres-Schumann S, Speese SD, Lora JM, Bastiani MJ. Characterization of two novel lipocalins expressed in the Drosophila embryonic nervous system. Int J Dev Biol. 2000;44:349–59. [PubMed] [Google Scholar]
  • 51.Ganfornina MD, Sanchez D, Pagano A, Tonachini L, Descalzi-Cancedda F, Martinez S. Molecular characterization and developmental expression pattern of the chicken apolipoprotein D gene: implications for the evolution of vertebrate lipocalins. Dev Dyn. 2005;232:191–9. doi: 10.1002/dvdy.20193. [DOI] [PubMed] [Google Scholar]
  • 52.Navarro A, Del Valle E, Tolivia J. Differential expression of apolipoprotein d in human astroglial and oligodendroglial cells. J Histochem Cytochem. 2004;52:1031–6. doi: 10.1369/jhc.3A6213.2004. [DOI] [PubMed] [Google Scholar]
  • 53.Sanchez D, Ganfornina MD, Martinez S. Expression pattern of the lipocalin apolipoprotein D during mouse embryogenesis. Mech Dev. 2002;110:225–9. doi: 10.1016/s0925-4773(01)00578-0. [DOI] [PubMed] [Google Scholar]
  • 54.Hull-Thompson J, Muffat J, Sanchez D, Walker DW, Benzer S, Ganfornina MD, et al. Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz. PLoS Genet. 2009;5:1000460. doi: 10.1371/journal.pgen.1000460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Wang MC, Bohmann D, Jasper H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell. 2005;121:115–25. doi: 10.1016/j.cell.2005.02.030. [DOI] [PubMed] [Google Scholar]
  • 56.Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc Natl Acad Sci USA. 2005;102:4494–9. doi: 10.1073/pnas.0500749102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Ganfornina MD, Do Carmo S, Lora JM, Torres-Schumann S, Vogel M, Allhorn M, et al. Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress. Aging Cell. 2008;7:506–15. doi: 10.1111/j.1474-9726.2008.00395.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Charron JB, Ouellet F, Houde M, Sarhan F. The plant Apolipoprotein D ortholog protects Arabidopsis against oxidative stress. BMC Plant Biol. 2008;8:86. doi: 10.1186/1471-2229-8-86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Charron JB, Ouellet F, Pelletier M, Danyluk J, Chauve C, Sarhan F. Identification, expression and evolutionary analyses of plant lipocalins. Plant Physiol. 2005;139:2017–28. doi: 10.1104/pp.105.070466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Muffat J, Walker DW, Benzer S. Human ApoD, an apolipoprotein upregulated in neurodegenerative diseases, extends lifespan and increases stress resistance in Drosophila. Proc Natl Acad Sci USA. 2008;105:7088–93. doi: 10.1073/pnas.0800896105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Frenette Charron JB, Breton G, Badawi M, Sarhan F. Molecular and structural analyses of a novel temperature stress-induced lipocalin from wheat and Arabidopsis. FEBS Lett. 2002;517:129–32. doi: 10.1016/s0014-5793(02)02606-6. [DOI] [PubMed] [Google Scholar]
  • 62.Do Carmo S, Levros LC, Jr, Rassart E. Modulation of apolipoprotein D expression and translocation under specific stress conditions. Biochim Biophys Acta. 2007;1773:954–69. doi: 10.1016/j.bbamcr.2007.03.007. [DOI] [PubMed] [Google Scholar]
  • 63.Do Carmo S, Jacomy H, Talbot PJ, Rassart E. Neuroprotective effect of apolipoprotein D against human coronavirus OC43-induced encephalitis in mice. J Neurosci. 2008;28:10330–8. doi: 10.1523/JNEUROSCI.2644-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Russell SJ, Kahn CR. Endocrine regulation of ageing. Nat Rev Mol Cell Biol. 2007;8:681–91. doi: 10.1038/nrm2234. [DOI] [PubMed] [Google Scholar]
  • 65.Do Carmo S, Fournier D, Mounier C, Rassart E. Human apolipoprotein D overexpression in transgenic mice induces insulin resistance and alters lipid metabolism. Am J Physiol Endocrinol Metab. 2009;296:802–11. doi: 10.1152/ajpendo.90725.2008. [DOI] [PubMed] [Google Scholar]
  • 66.Vogt M, Skerra A. Construction of an artificial receptor protein (“anticalin”) based on the human apolipoprotein D. Chembiochem. 2004;5:191–9. doi: 10.1002/cbic.200300703. [DOI] [PubMed] [Google Scholar]

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