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Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects (~700), including patients with SCZ, affective disorders and nonpsychiatric controls (from 14th gestational week to 85 years of age), and examined genotype-expression associations of 278 single-nucleotide polymorphisms (SNPs) located in or near DRD2 and DRD1 genes. Expression of D2S mRNA and D2S/D2-long (D2L) ratio were significantly increased in DLPFC of patients with SCZ relative to controls (P<0.0001 and P<0.0001, respectively), whereas D2L, D2Longer and DRD1 were decreased (P<0.0001). Patients with affective disorders showed an opposite pattern: reduced expression of D2S (major depressive disorder, P<0.0001) and increased expression of D2L and DRD1 (bipolar disorder, P<0.0001). Moreover, SCZ-associated risk alleles at rs1079727, rs1076560 and rs2283265 predicted increased D2S/D2L expression ratio (P<0.05) in control individuals. Our data suggest that altered splicing of DRD2 and expression of DRD1 may constitute a pathophysiological mechanism in risk for SCZ and affective disorders. The association between SCZ risk-associated polymorphism and the ratio of D2S/D2L is consistent with this possibility. [ABSTRACT FROM AUTHOR]

The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD. [ABSTRACT FROM AUTHOR]

Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK+)-containing form of trkB and measured pan trkC mRNA in schizophrenics (N=14) and controls (N=15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkBTK+ mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkBTK+ mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkBTK+ mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkBTK+ was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia.Molecular Psychiatry (2005) 10, 637–650. doi:10.1038/sj.mp.4001678 Published online 10 May 2005 [ABSTRACT FROM AUTHOR]

Anatomical and molecular abnormalities of excitatory neurons in the dorsolateral prefrontal cortex (DLPFC) are found in schizophrenia. We hypothesized that brain-derived neurotrophic factor (BDNF), a protein capable of increasing pyramidal neuron spine density and augmenting synaptic efficacy of glutamate, may be abnormally expressed in the DLPFC of patients with schizophrenia. Using an RNase protection assay and Western blotting, we detected a significant reduction in BDNF mRNA (mean = 23%) and protein (mean = 40%) in the DLPFC of patients with schizophrenia compared to normal individuals. At the cellular level, BDNF mRNA was expressed at varying intensities in pyramidal neurons throughout layers II, III, V, and VI of DLPFC. In patients with schizophrenia; neuronal BDNF expression was decreased in layers III, V and VI. Our study demonstrates a reduction in BDNF production and availability in the DLPFC of schizophrenics, and suggests that intrinsic cortical neurons, afferent neurons, and target neurons may receive less trophic support in this disorder. [ABSTRACT FROM AUTHOR]

Abstract Signalling through tyrosine kinase receptor B (trkB) influences neuronal survival, differentiation and synaptogenesis. trkB exists in a full-length form (trkBTK+ ), which contains a catalytic tyrosine kinase (TK) domain, and a truncated form (trkBTK– ), which lacks this domain. In the rodent brain, expression of trkBTK+ decreases and trkBTK– increases during postnatal life. We hypothesized that both forms of trkB receptor mRNA would be present in the human neocortex and that the developmental profile of trkB gene expression in human may be distinct from that in rodent. We detected both trkBTK+ and trkBTK– mRNA in RNA extracted from multiple human brain regions by Northern blot. Using in situ hybridization, we found trkBTK+ mRNA in all cortical layers, with highest expression in layer IV and intermediate-to-high expression in layers III and V of the human dorsolateral prefrontal cortex. trkBTK+ mRNA was present in neurons with both pyramidal and nonpyramidal shapes in the dorsolateral prefrontal cortex. trkBTK+ mRNA levels were significantly increased in layer III in young adults as compared with infants and the elderly. In the elderly, trkBTK+ mRNA levels were reduced markedly in all cortical layers. Unlike the mRNA encoding the full-length form of trkB, trkBTK– mRNA was distributed homogeneously across the grey matter, and trkBTK– mRNA levels increased only slightly during postnatal life. The results suggest that neurons in the human dorsolateral prefrontal cortex are responsive to neurotrophins throughout postnatal life and that this responsiveness may be modulated during the human lifespan. [ABSTRACT FROM AUTHOR]

We studied the sequence of several metabolic reactions, representative for oxidative damage and protection, in primary leaves of Phaseolus vulgaris (cv. Limburgse vroege) as a function of root assimilation of a toxic sublethal Cu concentration (630 μM). A transient increase of products of membrane peroxidation was observed in the primary leaves during the period of Cu uptake This rise was mainly due to the oxidizing properties of copper itself and not to a stimulation of the lipoxygenase (EC 1.13.11.12) activity. In our experimental conditions, membrane lipid peroxidation and K=-leakage were not directly related during at least three days after Cu application to the roots when products of lipid peroxidation were already detected in the leaf, permeability of the cytoplasmic membrane for K= was improved. However, Cu stimulated the capacity of catalase (EC 1.11.1.6) and ascorbate peroxidase (EC 1.11.1.11). These enzymes protect the tissue against oxidative stress since at least the hydrogen peroxide content was significantly reduced. Superoxide dismutase (EC 1.15.1.1) was not involved in this defense mechanism. [ABSTRACT FROM AUTHOR]