apoD Levels Research Articles

Plasma Apolipoprotein Levels Are Associated with Cognitive Status and Decline in a Community Cohort of Older Individuals

ObjectivesApolipoproteins have recently been implicated in the etiology of Alzheimer’s disease (AD). In particular, Apolipoprotein J (ApoJ or clusterin) has been proposed as a biomarker of the disease at the pre-dementia stage. We examined a group of apolipoproteins, including ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH and ApoJ, in the plasma of a longitudinal community based cohort.Methods664 subjects (257 with Mild Cognitive Impairment [MCI] and 407 with normal cognition), mean age 78 years, from the Sydney Memory and Aging Study (MAS) were followed up over two years. Plasma apolipoprotein levels at baseline (Wave 1) were measured using a multiplex bead fluorescence immunoassay technique.ResultsAt Wave 1, MCI subjects had lower levels of ApoA1, ApoA2 and ApoH, and higher levels of ApoE and ApoJ, and a higher ApoB/ApoA1 ratio. Carriers of the apolipoprotein E ε4 allele had significantly lower levels of plasma ApoE, ApoC3 and ApoH and a significantly higher level of ApoB. Global cognitive scores were correlated positively with ApoH and negatively with ApoJ levels. ApoJ and ApoE levels were correlated negatively with grey matter volume and positively with cerebrospinal fluid (CSF) volume on MRI. Lower ApoA1, ApoA2 and ApoH levels, and higher ApoB/ApoA1 ratio, increased the risk of cognitive decline over two years in cognitively normal individuals. ApoA1 was the most significant predictor of decline. These associations remained after statistically controlling for lipid profile. Higher ApoJ levels predicted white matter atrophy over two years.ConclusionsElderly individuals with MCI have abnormal apolipoprotein levels, which are related to cognitive function and volumetric MRI measures cross-sectionally and are predictive of cognitive impairment in cognitively normal subjects. ApoA1, ApoH and ApoJ are potential plasma biomarkers of cognitive decline in non-demented elderly individuals.

Proteomic Signature of Apolipoprotein J in the Early Phase of New-Onset Myocardial Infarction

Acute myocardial infarction (AMI) is one of the major causes of mortality and morbidity worldwide. Despite all the efforts, there is a lack of early markers for prevention, diagnosis, and treatment of ischemic syndromes. By applying a proteomic expression profiling approach to identify biomarkers of early stages of AMI, we have detected significant changes in Apolipoprotein J/clusterin (ApoJ) in patients with an acute new-onset myocardial infarction. ApoJ characterization by bidimensional electrophoresis (2-DE), followed by mass spectrometry (MALDI-TOF) depicted a cluster of 13 spots (pI, 4.5-5.0; M(w), 37.1-47.3 kDa) with a significantly different distribution between AMI-patients and controls. Specifically, spots 2, 3, 7, 10, and 13 showed a 2-fold increase in their intensity in AMI-patients (P = 0.001). Western-blot analysis (WB) for total serum ApoJ depicted two bands of 40-45 and 65-70 kDa. When only glycosylated forms were analyzed, the band of 65-70 kDa was the most predominant one. A 25% decrease (P = 0.05) of ApoJ glycosylated forms in AMI-patients was detected by 2-DE. Serum ApoJ levels, determined by a commercial ELISA, were significantly lower (P < 0.001) in AMI-patients (n = 39) immediately after the event than in controls (n = 60). In 60% of patients, the lowest ApoJ level was detected within 6 h after the onset of AMI. Between 72 and 96 h after admission, ApoJ values in AMI-patients had reached control levels. Our results demonstrate alterations in ApoJ proteomic profile, due to a differential glycosylation pattern, in AMI-patients within the first 6 h after the onset of the event. Therefore, the analysis of this isoform glycosylation shift in patients with AMI may be of better use to understand ApoJ function than the total serum levels of ApoJ and this isoform shift may become an early marker of AMI.

Downregulation of intracellular apolipoprotein D in DNA-PKcs-independent V(D)J recombination (36.16)

Abstract Recombination-inducible mouse pre-B cell lines are models for intracellular events that occur during lymphocyte V(D)J recombination. Using the ts-abl transformed pre-B cell lines with wild type DNA-PKcs or lines from SCID mice that have a DNA-PKcs deficiency, they can be induced to recombine their V(D)J genes segments. One of the events coincident with recombination is G1 cell cycle arrest that is much more dramatic in the SCID pre-B cells. We have recently become interested in intracellular apolipoprotein D (ApoD), an ancient intracellular lipocalin. ApoD has been described to have a role in extending lifespan by modulating cellular stress responses. ApoD would be expected to be upregulated in cells undergoing cell cycle arrest as this is a potentially stressful event for dividing cells. However, when assessing the effects of cell cycle arrest in the pre-B cell lines, we found that the intracellular Apo D actually decreases. The SCID pre-B cells, having a more severe G1 cycle arrest from recombination induction, also show a more dramatic reduction in ApoD levels. It is unclear whether the down-regulation of ApoD is associated with the recombination induction or the cell cycle arrest events. Since the SCID pre-B cells are deficient in DNA-PKcs function, it is tempting to speculate that ApoD gene expression may be influenced by this protein kinase. Nevertheless, these data suggest a previously undescribed role for intracellular ApoD in B-cell V(D)J recombination events.

Effects of chronic Clozapine administration on apolipoprotein D levels and on functional recovery following experimental stroke

Elevated brain levels of apolipoprotein D (ApoD) correlate with improved neurological recovery after experimental stroke. Hence, a pharmacological induction of ApoD in the postischemic brain could be beneficial for recovery after stroke. Here we investigated the effect of Clozapine, a compound that increases the expression of ApoD, in two rat models of experimental stroke. Rats were subjected to permanent occlusion of the middle cerebral artery (pMCAO) and treated with Clozapine (i.p. 10 mg/kg body weight) or saline for 8 or 28 days starting on the second day after MCAO. ApoD levels increased by 35% in the peri-infarct area after 10 and 30 days after pMCAO, mainly in neuron-specific nuclear protein (NeuN) positive neurons and glial fibrillary acidic protein (GFAP) positive astrocytes . Clozapine did not affect the neurological deficit assessed by the rotating pole test and a grip strength test at 7 days, 14 days, 21 days, and 28 days after pMCAO. Functional outcome and the infarct size were similar in rats subjected to transient MCAO and injected with Clozapine (i.p. 10 mg/kg body weight) or saline for 26 days starting on the second day after tMCAO. We conclude that Clozapine affects cellular processes involved in peri-infarct tissue reorganization, but does not affect functional recovery after MCAO.

Decreased kainate receptors in the hippocampus of apolipoprotein D knockout mice

Apolipoprotein D (ApoD) has many actions critical to maintaining mammalian CNS function. It is therefore significant that levels of ApoD have been shown to be altered in the CNS of subjects with schizophrenia, suggesting a role for ApoD in the pathophysiology of the disorder. There is also a large body of evidence that cortical and hippocampal glutamatergic, serotonergic and cholinergic systems are affected by the pathophysiology of schizophrenia. Thus, we decided to use in vitro radioligand binding and autoradiography to measure levels of ionotropic glutamate, some muscarinic and serotonin 2A receptors in the CNS of ApoD(-/-) and isogenic wild-type mice. These studies revealed a 20% decrease (mean+/-SEM: 104+/-10.2 vs. 130+/-10.4 fmol/mg ETE) in the density of kainate receptors in the CA 2-3 of the ApoD(-/-) mice. In addition there was a global decrease in AMPA receptors (F(1,214)=4.67, p<0.05) and a global increase in muscarinic M2/M4 receptors (F(1,208)=22.77, p<0.0001) in the ApoD(-/-) mice that did not reach significance in any single cytoarchitectural region. We conclude that glutamatergic pathways seem to be particularly affected in ApoD(-/-) mice and this may contribute to the changes in learning and memory, motor tasks and orientation-based tasks observed in these animals, all of which involve glutamatergic neurotransmission.

Modulation of Apolipoprotein D levels in human pregnancy and association with gestational weight gain

BackgroundApolipoprotein D (ApoD) is a lipocalin involved in several processes including lipid transport, but its modulation during human pregnancy was never examined.MethodsWe investigated the changes in the levels of ApoD in the plasma of pregnant women at the two first trimesters of gestation and at delivery as well as in the placenta and in venous cord blood. These changes were studied in 151 women classified into 9 groups in relation to their prepregnancy body mass index (BMI) and gestational weight gain (GWG).ResultsPlasma ApoD levels decrease significantly during normal uncomplicated pregnancy. ApoD is further decreased in women with excessive GWG and their newborns. In these women, the ApoD concentration was tightly associated with the lipid parameters. However, the similar ApoD levels in low cholesterol (LC) and high cholesterol (HC) women suggest that the plasma ApoD variation is not cholesterol dependant. A tight regulation of both placental ApoD transcription and protein content is most probably at the basis of the low circulating ApoD concentrations in women with excessive GWG. After delivery, the plasma ApoD concentrations depended on whether the mother was breast-feeding or not, lactation favoring a faster return to baseline values.ConclusionIt is speculated that the decrease in plasma ApoD concentration during pregnancy is an adaptive response aimed at maintaining fetal lipid homeostasis. The exact mechanism of this adaptation is not known.

The HDL proteome: a marker–and perhaps mediator–of coronary artery disease

One important cardioprotective function of HDL is to remove cholesterol from lipid-laden macrophages in the artery wall. HDL also exerts anti-inflammatory effects that might inhibit atherogenesis. However, HDL has been proposed to be dysfunctional in humans with established coronary artery disease (CAD), though the underlying mechanisms are unclear. Therefore, we used mass spectrometry to investigate the roles of HDL proteins in inflammation and cardiovascular disease. Shotgun proteomic analysis identified multiple complement regulatory proteins, protease inhibitors, and acute-phase response proteins in HDL, strongly implicating the lipoprotein in inflammation and the innate immune system. Moreover, mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with clinically significant CAD was selectively enriched in apolipoprotein E, suggesting that it carries a distinctive protein cargo in humans with atherosclerosis. HDL from CAD subjects also contained markedly elevated levels of chlorotyrosine and nitrotyrosine, two characteristic products of myeloperoxidase, indicating that oxidative damage might generate dysfunctional HDL. Aggressive lipid therapy with a statin and niacin remodeled the HDL proteome to resemble that of apparently healthy subjects. Collectively, our observations indicate that quantifying the HDL proteome by mass spectrometry should help identify novel anti-inflammatory and cardioprotective actions of HDL and provide insights into lipid therapy.

Apolipoprotein D is Elevated in Oligodendrocytes in the Peri-Infarct Region after Experimental Stroke: Influence of Enriched Environment

Injury to the brain (e.g., stroke) results in a disruption of neuronal connectivity and loss of fundamental sensori-motor functions. The subsequent recovery of certain functions involves structural rearrangements in areas adjacent to the infarct. This remodeling of the injured brain requires trafficking of macromolecular components including cholesterol and phospholipids, a transport carried out by apolipoproteins including apolipoprotein D (apoD). We investigated the changes in the levels of apoD mRNA and protein, and its cellular localization during a recovery period up to 30 days after experimental stroke in the rat brain. In the core of the brain infarct, apoD immunoreactivity but not mRNA increased in dying pyramidal neurons, indicative of cellular redistribution of lipids. During 2 to 7 days of recovery after stroke, the apoD levels increased in the peri-infarct and white matter areas in cells identified as mature oligodendrocytes. The apoD expressing cells were conspicuously located along the rim of the infarct, suggesting a role for apoD in tissue repair. Furthermore, housing animals in an enriched environment improved sensori-motor function and increased the apoD levels. Our data strongly suggest that apoD is involved in regenerative processes and scar formation in the peri-infarct area presumably by enhancing lipid trafficking.

Gene expression pathways induced by axotomy and decentralization of rat superior cervical ganglion neurons

To identify genes potentially involved in remodelling synaptic connections, we induced the temporary detachment of pre- and post-synaptic elements by axotomy or denervation of rat superior cervical ganglion neurons. cDNA microarray analysis followed by stringent selection criteria allowed the identification of a panel of genes whose expression was modulated by axotomy at various time points after injury. Among these genes, 11 were validated by real-time reverse transcriptase-polymerase chain reaction on independently prepared samples after superior cervical ganglion neuron axotomy (1, 3 and 6 days) and compared with the effect of decentralization (8 h, 1 and 3 days). These genes code for extracellular matrix/space [apolipoprotein D (apoD), decorin, collagen alpha1 type I, collagen alpha1 type III] and intermediate filament (vimentin) proteins, for modulators of neurite outgrowth (thrombin receptor, plasminogen activator inhibitor-1, bone morphogenetic protein 4, annexin II and S-100-related protein, clone 42C) and for a nerve cell transcription factor (brain finger protein). Eight of these 11 genes showed significant and persistent modulations after both types of injury. Finally, protein levels of apoD were shown to increase in superior cervical ganglion after axotomy. Our results identify hitherto unrecorded genes responsive to axotomy and decentralization of superior cervical ganglion neurons, and probably involved in synapse formation, remodelling and elimination.

Effects of caloric restriction and gender on rat serum paraoxonase 1 activity

Paraoxonase 1 (PON1) associates to specific high-density lipoproteins (HDLs) — those containing apolipoprotein A-I (apoA-I) and apolipoprotein J (apoJ) — and is largely responsible for their antiatherogenic properties. Caloric restriction (CR) has been shown to reduce major atherosclerotic risk factors. The aims of this work were to study PON1 activity response to CR (40% over 14 weeks) and to elucidate whether there are adaptive differences related to gender. Serum and liver paraoxonase and arylesterase activities, serum triglyceride, total and HDL cholesterol concentrations, serum PON1, apoA-I and apoJ contents and liver PON1 mRNA levels were measured. No effects of CR or gender were observed in triglyceride, total cholesterol concentration and PON1 mRNA levels. HDL cholesterol was higher in female rats than in male rats and increased with CR only in the latter animals. Serum PON1 activities tended to be higher in female rats and dropped with CR, with females showing the biggest decrease. Serum PON1 content was higher in female rats and decreased in both genders with CR, whereas apoA-I and apoJ contents, which were higher in female rats too, decreased only in the former animals, accounting for the high PON1 activity decrease observed in these animals. In conclusion, the short-term CR-associated reduction of serum PON1 activity and PON1, apoA-I and apoJ levels points toward a reduced stability of HDL–PON1 complexes and/or HDL particle levels responsible for PON1 transport and function in the blood. Moreover, the variations in PON1 activity and apolipoprotein levels show gender-related differences that are indicative of a different adaptive strategy of male and female rats when faced with a period of food restriction.

Proteomic Analysis to Identify Breast Cancer Biomarkers in Nipple Aspirate Fluid

Proteomic analysis of breast nipple aspirate fluid (NAF) holds promise as a noninvasive method to identify markers of breast cancer. The objectives of the study were to: (a) describe the NAF proteome, (b) identify candidate markers of breast cancer in NAF by using proteomic analysis, and (c) validate the markers identified by using a quantitative, high-throughput ELISA analysis. For proteome analysis, NAF proteins from a single subject without breast cancer were separated by two-dimensional PAGE and were subjected to matrix-assisted laser desorption ionization time-of-flight mass spectometry identification. A total of 41 different proteins were identified, 25 of which were known to be secreted. To identify breast cancer markers, we separated 20 NAF samples (10 normal, 10 cancer) by two-dimensional PAGE. Three protein spots were detected that were up-regulated in three or more cancer samples. These spots were identified to be gross cystic disease fluid protein (GCDFP)-15, apolipoprotein D (apoD), and alpha1-acid glycoprotein (AAG). To validate these three potential biomarkers, 105 samples (53 from benign breasts and 52 from breasts with cancer) were analyzed using ELISA. Among all of the subjects, GCDFP-15 levels were lower (P <0.001) and AAG levels were higher (P=0.001) in breasts with cancer. This was also true in premenopausal (GCDFP-15, P=0.011; AAG, P=0.002) but not in postmenopausal women. GCDFP-15 levels were lowest (P=0.003) and AAG levels highest (P <0.001) in women with ductal carcinoma in situ (DCIS). Menopausal status influenced GCDFP-15 and AAG more in women without breast cancer than in women with breast cancer. apoD levels did not correlate significantly with breast cancer. Our study revealed that the NAF proteome, as defined by two-dimensional PAGE, consists of a limited number of proteins, and that the expression of AAG and GCDFP-15 correlates with disease presence and stage.

Deficiency of ABCA1 Impairs Apolipoprotein E Metabolism in Brain

ABCA1 is a cholesterol transporter that is widely expressed throughout the body. Outside the central nervous system (CNS), ABCA1 functions in the biogenesis of high-density lipoprotein (HDL), where it mediates the efflux of cholesterol and phospholipids to apolipoprotein (apo) A-I. Deficiency of ABCA1 results in lack of circulating HDL and greatly reduced levels of apoA-I. ABCA1 is also expressed in cells within the CNS, but its roles in brain lipid metabolism are not yet fully understood. In the brain, glia synthesize the apolipoproteins involved in CNS lipid metabolism. Here we demonstrate that glial ABCA1 is required for cholesterol efflux to apoA-I and plays a key role in facilitating cholesterol efflux to apoE, which is the major apolipoprotein in the brain. In both astrocytes and microglia, ABCA1 deficiency reduces lipid efflux to exogenous apoE. The impaired ability to efflux lipids in ABCA1-/- glia results in lipid accumulation in both astrocytes and microglia under normal culture conditions. Additionally, apoE secretion is compromised in ABCA1-/- astrocytes and microglia. In vivo, deficiency of ABCA1 results in a 65% decrease in apoE levels in whole brain, and a 75-80% decrease in apoE levels in hippocampus and striatum. Additionally, the effect of ABCA1 on apoE is selective, as apoJ levels are unchanged in brains of ABCA1-/- mice. Taken together, these results show that glial ABCA1 is a key influence on apoE metabolism in the CNS.

Association of plasma apolipoproteins D with RBC membrane arachidonic acid levels in schizophrenia

Apolipoprotein D (apoD) is a member of the lipocalin superfamily of transporter proteins that bind small hydrophobic molecules, including arachidonic acid (AA). The ability of apoD to bind AA implicates it in pathways associated with membrane phospholipid signal transduction and metabolism. Recent findings of an increased expression of apoD in the mouse brain after clozapine treatment suggested a role for apoD in the pharmacological action of clozapine. Moreover, clozapine has been shown to increase membrane AA levels in RBC phospholipids from schizophrenic patients. ApoD levels have also been shown to be elevated in the CNS of subjects with chronic schizophrenia, a disorder associated with AA dysfunction. In this study, we examined whether plasma apoD levels are related to red blood cell membrane AA contents in the first-episode neuroleptic-naïve schizophrenic (FENNS) patients. Plasma apoD levels as measured by enzyme-linked immunosorbent assay (ELISA) were not significantly different ( F=0.51, df=2,86, p=0.60) among healthy controls ( n=36), FENNS patients ( n=33) and patients with other psychiatric disorders ( n=19). However, plasma apoD levels were significantly correlated with RBC-AA ( p=0.0022) and docosapentaenoic acid ( p=0.0008) in FENNS patients. There are several known mechanisms that can lead to the type of membrane fatty acid defects that have been identified in schizophrenia. Whether plasma apoD alone is a major determinant of reduced RBC membrane AA levels in FENNS patients remains to be determined, although these preliminary data appear not to support this premise. Taken together with other in vitro studies, however, the present data support the view that an increased expression of apoD such as induced by atypical neuroleptic drug, may facilitate incorporation of AA into membrane phospholipids by its selective binding to AA.

Apolipoprotein-D: a novel cellular marker for HGPIN and prostate cancer.

High grade prostatic intraepithelial neoplasia (HGPIN) is a putative pre-malignant lesion of the prostate. While apolipoprotein-D (Apo-D), an androgen-regulated hydrophobic transporter protein, is expressed in prostate tumors, its expression in HGPIN is unknown. Immunoreactivity for Apo-D and another androgen-regulated protein, prostate specific antigen (PSA), was investigated in 64 radical prostatectomy tissues by video image analysis. Eighty two percent of prostatectomy specimens demonstrated moderate to strong Apo-D immunoreactivity in areas of HGPIN. In comparison, weak Apo-D immunoreactivity was observed in non-malignant areas in only 24% of specimens. The median (range) percentage cellular area of HGPIN immunopositive for Apo-D (9.7%, 0-42.9), and the cellular concentration of Apo-D (MIOD 3.1, 0-13.3), were intermediate between that of normal (area 0%, 0-53.5%, MIOD 0, 0-12.6) and early stage prostate cancer tissues (area 29.2%, 0-90.8%, MIOD 6.7, 0-28.1). This increase in Apo-D expression from non-malignant, through HGPIN to prostate cancer was statistically significant (P < 0.001), and contrasted with the decrease observed in PSA staining between adjacent areas of normal glands, HGPIN, and cancer (P = 0.026). The presence of high levels of immunoreactive Apo-D in HGPIN and prostate cancer, but not in non-malignant epithelial cells, is consistent with HGPIN being an intermediate lesion in the transition to prostate cancer, and suggests that cellular Apo-D expression is a marker of malignant transformation of the prostate.

Hippocampal apolipoprotein D level depends on Braak stage and APOE genotype

Apolipoprotein (APO, gene; apo, protein) D, a member of the lipocalin family, has been implicated in several, pathological conditions but neither its physiologic function(s) nor ligand(s) has been clearly identified so far. Presuming a role in nerve de- and regeneration, several groups investigated apoD alterations in Alzheimer's disease (AD). Reported data, however, were not unanimous. We determined apoD protein levels in the hippocampus in a large, carefully matched autopsy case sample. ApoD levels were compared with the severity of neuropathological changes as determined by the Braak classification and with APOE genotype, a major risk factor for developing AD. ApoD was found to be related to the severity of AD-related neurofibrillary (NF) changes and not to old age alone. No correlation was found to amyloid deposits. Brain samples with widespread NF changes showed significantly higher apoD than cases with low Braak stages. This increase, however, was restricted to the APOE ϵ3/3 group, whereas the APOE ϵ4 group did not show significant variations in hippocampal apoD.

Antipsychotic drugs differentially modulate apolipoprotein D in rat brain.

Apolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.

Apolipoprotein D levels are elevated in prefrontal cortex of subjects with Alzheimer’s disease: no relation to apolipoprotein E expression or genotype

Background Apolipoprotein E (apoE) has been implicated in the pathology of AD ever since inheritance of the ε4 allele was shown to be an important risk factor for the development of AD. Apolipoprotein D (apoD) is elevated in association with several central nervous system disorders, including Alzheimer’s disease (AD), and has been proposed to be an especially robust marker for brain regions specifically affected by particular neuropathologies. Progressive cognitive decline is the core clinical feature of AD and is associated with disturbances in the prefrontal cortex. Methods We measured apoD levels in prefrontal cortex samples obtained postmortem from 20 autopsy-confirmed AD subjects and 40 control subjects. Results Enzyme-linked immunosorbent assay analysis revealed a significant increase in apoD expression in AD subjects compared with control subjects (.218 ± .029 μg/mg protein vs. .117 ± .011 μg/mg protein; p = .0003). There was no significant difference in apoD expression between early-onset and late-onset Alzheimer’s subjects. Apolipoprotein D expression levels were not correlated with apoE levels, nor were they correlated with inheritance of the APOE ε4 allele. Conclusions These findings suggest that apoD may be related to the cognitive decline observed in AD patients and that apoD and apoE likely play different roles in the pathogenesis of AD.

Differences in neuroanatomical sites of apoD elevation discriminate between schizophrenia and bipolar disorder.

We previously demonstrated that apolipoprotein D (apoD) levels are elevated in the dorsolateral prefrontal cortex and caudate obtained postmortem from subjects with schizophrenia and bipolar disorder compared to controls, suggesting a focal compensatory response to neuropathology associated with psychiatric disorders. We have now extended those studies by measuring apoD protein levels in additional brain regions from post-mortem samples of schizophrenic and bipolar disorder subjects using an enzyme-linked immunosorbent assay. Increased apoD levels were observed in the lateral prefrontal cortex (Brodmann Area 46) in both schizophrenia (46%) and bipolar disorder (111%), and in the orbitofrontal cortex (Brodmann Area 11) (44.3 and 37.9% for schizophrenia and bipolar disorder, respectively). However, differences between the disease groups were observed in other brain regions. In subjects with schizophrenia, but not bipolar disorder, apoD levels were significantly elevated in the amygdala (42.8%) and thalamus (31.7%), while in bipolar disorder, but not schizophrenia, additional increases were detected in the parietal cortex (Brodmann Area 40; 123%) and the cingulate cortex (Brodmann Area 24; 57.7%). These data demonstrate that there is anatomical overlap in the pathophysiologies of schizophrenia and bipolar disorder, as well as areas of pathology that distinguish the two disorders.

Serum levels of the senescence biomarker clusterin/apolipoprotein J increase significantly in diabetes type II and during development of coronary heart disease or at myocardial infarction

Clusterin/apolipoprotein J (hereafter ApoJ) is a conserved secreted glycoprotein expressed by a wide array of tissues and being implicated in several physiological processes. ApoJ has been shown to associate with both normal in vitro aging, namely replicative senescence, as well as with stress induced premature senescence. In vivo, the protein is up-regulated in many severe physiological disturbances that relate to advanced aging, including accumulation in the artery wall during the development of atherosclerosis. In the current report we have expanded our previous studies that focus in the biological role of ApoJ during aging by addressing two interrelated issues: (a) we have examined the potential ApoJ association with in vivo aging and (b) we have studied whether its accumulation in the artery wall during the development of atherosclerosis is combined with a measurable increase of its serum levels, as well as, whether a similar effect occurs in diseases, such as diabetes type II, known to represent major risk factors of atherosclerosis. By combining a sandwich ELISA assay and immunoblotting analysis we demonstrate a measurable increase of ApoJ serum levels with age in males and provide evidence that, as compared to healthy donors, the serum ApoJ amount increases significantly in diabetic type II patients and in patients suffering from either a developing coronary heart disease, or myocardial infarction. The highest serum ApoJ levels were found during myocardial infarction but no correlation was observed with the number of vessels with documented atherosclerotic damage. In conclusion, this report illustrates that ApoJ accumulation in serum is probably coupled to a generalized stress mediated induction mechanism that is specifically related to certain diseases; moreover these data raise the possibility that elevated ApoJ levels in serum may represent a strong indication of vascular damage.

Elevated plasma level of apolipoprotein D in schizophrenia and its treatment and outcome

Recently, apolipoprotein D (apoD), a protein that is involved in the essential polyunsaturated fatty acid (EPUFA) transport and metabolism, and neuronal growth and regeneration was reported to have increased in the postmortem brain and decreased in the serum of schizophrenia patients. We studied the plasma apoD levels in never-medicated schizophrenic patients at the onset of psychosis and in chronic patients with clozapine treatment. Plasma apoD levels were elevated in never-medicated patients at the first-episode of psychosis compared to normals ( P=0.047). Interestingly, the increase in apoD level was even more significant in chronic patients treated with clozapine compared to normals and first-episode patients ( P=0.008 and P=0.03, respectively). The increased apoD level in never-medicated first-episode patients indicate that this increase probably predates the illness, since the duration of illness was <5 days. Similarly, an even larger increase in apoD after clozapine treatment may be associated with its prophylactic effects, since the psychopathological scores were significantly reduced and the clozapine treatment has been found to increase the EPUFA membrane levels. These altered levels of apoD may help to understand the nature and possible mechanism of phospholipid membrane pathology in schizophrenia.