| APC |
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| 1 | | Neurochem. Res. 2004 Dec 29: 2293-302 |
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| PMID | 15672553 |
| Title | Altered myelination of the hippocampal formation in subjects with schizophrenia and bipolar disorder. |
| Abstract | Myelination of the frontal and temporal lobes occurs at a similar time period as symptom onset in schizophrenia. To assess this potential relationship, we compared myelination and oligodendrocyte numbers in the hippocampal formation of controls and matched subjects with schizophrenia and bipolar disorder. The levels and distribution of the myelin marker myelin basic protein (MBP) and the oligodendrocyte marker adenomatous polyposis coli (APC) were measured using immunocytochemistry. MBP immunoreactivity (IR) was increased in several hippocampal subregions of control females versus control males. Female subjects with schizophrenia and bipolar disorder exhibited decreased myelination in the hippocampal formation while male subjects with bipolar disorder showed increased MBP levels in the superior medullary lamina. In contrast, the number of APC immunoreactive cells did not differ in any disorder or region. Our results demonstrate an interaction between gender, mental illness, and myelination, and may be related to cognitive deficits seen in schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 2 | | Mol. Psychiatry 2005 Jul 10: 669-77 |
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| PMID | 15768050 |
| Title | The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia. |
| Abstract | The etiology of schizophrenia is unclear, although family, twin, and linkage studies implicate genetic factors. Here, we identified adenomatous polyposis coli (APC), a tumor suppressor gene, as a risk factor for schizophrenia. We compared leukocytic gene expression patterns of six pairs of patients with schizophrenia and healthy controls by microarray. APC expression levels were significantly increased in all patients compared to healthy controls. To confirm the findings of microarray analysis, we measured expression levels of APC in the leukocytes from 30 relapse patients taking antipsychotic medication, 29 first-episode drug-naïve patients, and 30 healthy controls using real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR). APC expression levels were significantly increased in leukocytes of schizophrenics both taking and not taking antipsychotic medication and hence the increase of APC expression was not due to antipsychotic medication. APC is located at 5q21-22, which has been previously reported to be linked with schizophrenia. Further, we performed the transmission disequilibrium test (TDT) and TDT based on haplotypes to search for the association between schizophrenia and APC by examining 163 parent-offspring trios of Chinese descent. We analyzed three single-nucleotide polymorphisms (SNPs) (rs2229992, rs42427, rs465899) at the exon region of APC. TDT showed that the three SNPs are significantly associated with schizophrenia (TDT chi(2)=4.23, P<0.05; 4.15, P<0.05; 8.49 P<0.01, respectively; HHRRchi(2)=5.54, P<0.05; 4.40, P<0.05; 9.79, P<0.01, respectively). We found a significant association between the APC haplotypes from rs2229992-rs42427-rs465899 and schizophrenia (Global chi(2)=44.376,df=7, P<0.001). The C-A-T haplotype has a frequency of more than 57% and has a strong association with schizophrenia (chi(2)=15.04, P<0.001). These results indicate that the APC may be a candidate gene conferring susceptibility to schizophrenia and also may be associated with reduced vulnerability to cancer in schizophrenia. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 3 | | Mol. Psychiatry 2005 Jul 10: 669-77 |
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| PMID | 15768050 |
| Title | The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia. |
| Abstract | The etiology of schizophrenia is unclear, although family, twin, and linkage studies implicate genetic factors. Here, we identified adenomatous polyposis coli (APC), a tumor suppressor gene, as a risk factor for schizophrenia. We compared leukocytic gene expression patterns of six pairs of patients with schizophrenia and healthy controls by microarray. APC expression levels were significantly increased in all patients compared to healthy controls. To confirm the findings of microarray analysis, we measured expression levels of APC in the leukocytes from 30 relapse patients taking antipsychotic medication, 29 first-episode drug-naïve patients, and 30 healthy controls using real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR). APC expression levels were significantly increased in leukocytes of schizophrenics both taking and not taking antipsychotic medication and hence the increase of APC expression was not due to antipsychotic medication. APC is located at 5q21-22, which has been previously reported to be linked with schizophrenia. Further, we performed the transmission disequilibrium test (TDT) and TDT based on haplotypes to search for the association between schizophrenia and APC by examining 163 parent-offspring trios of Chinese descent. We analyzed three single-nucleotide polymorphisms (SNPs) (rs2229992, rs42427, rs465899) at the exon region of APC. TDT showed that the three SNPs are significantly associated with schizophrenia (TDT chi(2)=4.23, P<0.05; 4.15, P<0.05; 8.49 P<0.01, respectively; HHRRchi(2)=5.54, P<0.05; 4.40, P<0.05; 9.79, P<0.01, respectively). We found a significant association between the APC haplotypes from rs2229992-rs42427-rs465899 and schizophrenia (Global chi(2)=44.376,df=7, P<0.001). The C-A-T haplotype has a frequency of more than 57% and has a strong association with schizophrenia (chi(2)=15.04, P<0.001). These results indicate that the APC may be a candidate gene conferring susceptibility to schizophrenia and also may be associated with reduced vulnerability to cancer in schizophrenia. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 4 | | Can J Psychiatry 2007 Mar 52: 182-90 |
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| PMID | 17479527 |
| Title | Treating delusional disorder: a comparison of cognitive-behavioural therapy and attention placebo control. |
| Abstract | Cognitive-behavioural therapy (CBT) has proved effective in treating delusions, both in schizophrenia and delusional disorder (DD). Clinical trials of DD have mostly compared CBT with either treatment as usual, no treatment, or a wait-list control. This current study aimed to assess patients with DD who received CBT, compared with an attention placebo control (APC) group.
Twenty-four individuals with DD were randomly allocated into either CBT or APC groups for a 24-week treatment period. Patients were diagnosed on the basis of structured clinical interviews for mental disorders and the Maudsley Assessment of Delusion Schedule (MADS).
Completers in both groups (n = 11 for CBT; n = 6 for APC) showed clinical improvement on the MADS dimensions of Strength of Conviction, Insight, Preoccupation, Systematization, Affect Relating to Belief, Belief Maintenance Factors, and Idiosyncrasy of Belief.
When compared with APC, CBT produced more impact on the MADS dimensions for Affect Relating to Belief, Strength of Conviction, and Positive Actions on Beliefs. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 5 | | J. Mol. Neurosci. 2009 May 38: 2-11 |
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| PMID | 18836851 |
| Title | Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro. |
| Abstract | The discoidin domain receptor (DDR1) is highly expressed in oligodendrocytes during the neurodevelopmental myelination process and is genetically associated to schizophrenia. In this study, we aimed to further assess the involvement of DDR1 in both remyelination and oligodendrocyte differentiation. In the mouse model of demyelination-remyelination induced by oral administration of cuprizone, in situ hybridization showed an upregulation of the DDR1 gene in three different white matter areas (corpus callosum, dorsal fornix, and external capsule) during the remyelination period. Moreover, real time reverse transcriptase polymerase chain reaction showed that the increase in DDR1 messenger RNA (mRNA) was strongly correlated with the number of DDR1-positive cells in the corpus callosum (Spearman coefficient = 0.987, P = 0.013). Cells positive for DDR1 mRNA were also positive for oligodendrocyte markers (OLIG2, carnosine, and APC) but not for markers of oligodendrocyte precursors (NG2), myelin markers (CNPase), microglia (CD11b), or reactive glia (GFAP). Differentiation of a human oligodendroglial cell line, HOG16, was associated with an increase in mRNA expression of DDR1 and several myelin proteins (MBP and MOBP) but not other proteins (APC and CNPase). Here, we demonstrate that DDR1 is upregulated in vitro and in vivo when oligodendrocyte myelinating machinery is activated. Further studies are needed to identify the specific molecular pathway. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 6 | | Front Behav Neurosci 2011 -1 5: 85 |
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| PMID | 22347851 |
| Title | Adenomatous polyposis coli heterozygous knockout mice display hypoactivity and age-dependent working memory deficits. |
| Abstract | A tumor suppressor gene, Adenomatous polyposis coli (Apc), is expressed in the nervous system from embryonic to adulthood stages, and transmits the Wnt signaling pathway in which schizophrenia susceptibility genes, including T-cell factor 4 (TCF4) and calcineurin (CN), are involved. However, the functions of Apc in the nervous system are largely unknown. In this study, as the first evaluation of Apc function in the nervous system, we have investigated the behavioral significance of the Apc gene, applying a battery of behavioral tests to Apc heterozygous knockout (Apc(+/-)) mice. Apc(+/-) mice showed no significant impairment in neurological reflexes or sensory and motor abilities. In various tests, including light/dark transition, open-field, social interaction, eight-arm radial maze, and fear conditioning tests, Apc(+/-) mice exhibited hypoactivity. In the eight-arm radial maze, Apc(+/-) mice 6-7 weeks of age displayed almost normal performance, whereas those 11-12 weeks of age showed a severe performance deficit in working memory, suggesting that Apc is involved in working memory performance in an age-dependent manner. The possibility that anemia, which Apc(+/-) mice develop by 17 weeks of age, impairs working memory performance, however, cannot be excluded. Our results suggest that Apc plays a role in the regulation of locomotor activity and presumably working memory performance. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 7 | | Brain Res. 2011 Apr 1385: 281-92 |
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| PMID | 21338586 |
| Title | MK-801 induces schizophrenic behaviors through downregulating Wnt signaling pathways in male mice. |
| Abstract | Wnt signaling is important in various neuropsychiatric diseases. However, its actions on modulating schizophrenia are largely unknown. Our previous study found that three SNPs in adenomatous polyposis coli (APC), a negative regulator of the Wnt signaling, were associated with schizophrenia, and the mRNA levels of APC in blood leucocytes of patients with schizophrenia were significantly increased. This prompted us to further investigate the effects of Wnt signaling components on the pathogenesis of schizophrenia. In our current study, mouse schizophrenia was induced by i.p. injection of MK-801 for 7days and the brain prefrontal cortex (PFC) and ventral tegmental area (VTA) were isolated to investigate the Wnt signaling pathway. Compared with control, schizophrenic mice had increased inhibitory phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) in PFC and VTA, which is disassociated with augmented beta-catenin phosphorylation. However, APC mRNA and protein in the PFC and VTA isolated from the schizophrenic group were increased and matched with increased beta-catenin phosphorylation. The total dendritic length was significantly increased in both PFC and VTA from MK-801-treated mice compared to control. By using cultured SK-N-SH and PC12 cells with and without transfection of APC siRNA, we found that the APC protein facilitates neurite growth in vitro. Our data suggested that MK-801-induced schizophrenia is associated with attenuated Wnt signaling pathway in the brain, which may be due to augmented APC protein during schizophrenia. APC facilitates neurite growth, potentially contributing to the pathology of schizophrenia. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 8 | | Brain Res. 2011 Apr 1385: 281-92 |
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| PMID | 21338586 |
| Title | MK-801 induces schizophrenic behaviors through downregulating Wnt signaling pathways in male mice. |
| Abstract | Wnt signaling is important in various neuropsychiatric diseases. However, its actions on modulating schizophrenia are largely unknown. Our previous study found that three SNPs in adenomatous polyposis coli (APC), a negative regulator of the Wnt signaling, were associated with schizophrenia, and the mRNA levels of APC in blood leucocytes of patients with schizophrenia were significantly increased. This prompted us to further investigate the effects of Wnt signaling components on the pathogenesis of schizophrenia. In our current study, mouse schizophrenia was induced by i.p. injection of MK-801 for 7days and the brain prefrontal cortex (PFC) and ventral tegmental area (VTA) were isolated to investigate the Wnt signaling pathway. Compared with control, schizophrenic mice had increased inhibitory phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) in PFC and VTA, which is disassociated with augmented beta-catenin phosphorylation. However, APC mRNA and protein in the PFC and VTA isolated from the schizophrenic group were increased and matched with increased beta-catenin phosphorylation. The total dendritic length was significantly increased in both PFC and VTA from MK-801-treated mice compared to control. By using cultured SK-N-SH and PC12 cells with and without transfection of APC siRNA, we found that the APC protein facilitates neurite growth in vitro. Our data suggested that MK-801-induced schizophrenia is associated with attenuated Wnt signaling pathway in the brain, which may be due to augmented APC protein during schizophrenia. APC facilitates neurite growth, potentially contributing to the pathology of schizophrenia. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 9 | | Cell Rep 2014 Apr 7: 552-64 |
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| PMID | 24726361 |
| Title | Dendrite development regulated by the schizophrenia-associated gene FEZ1 involves the ubiquitin proteasome system. |
| Abstract | Downregulation of the schizophrenia-associated gene DISC1 and its interacting protein FEZ1 positively regulates dendrite growth in young neurons. However, little is known about the mechanism that controls these molecules during neuronal development. Here, we identify several components of the ubiquitin proteasome system and the cell-cycle machinery that act upstream of FEZ1. We demonstrate that the ubiquitin ligase cell division cycle 20/anaphase-promoting complex (Cdc20/APC) controls dendrite growth by regulating the degradation of FEZ1. Furthermore, dendrite growth is modulated by BubR1, whose known function so far has been restricted to control Cdc20/APC activity during the cell cycle. The modulatory function of BubR1 is dependent on its acetylation status. We show that BubR1 is deacetylated by Hdac11, thereby disinhibiting the Cdc20/APC complex. Because dendrite growth is affected both in hippocampal dentate granule cells and olfactory bulb neurons upon modifying expression of these genes, we conclude that the proposed mechanism governs neuronal development in a general fashion. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 10 | |
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| PMID | 24678719 |
| Title | Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia. |
| Abstract | Loss of adenomatous polyposis coli (APC) gene function results in constitutive activation of the canonical Wnt pathway and represents the main initiating and rate-limiting event in colorectal tumorigenesis. APC is likely to participate in a wide spectrum of biological functions via its different functional domains and is abundantly expressed in the brain as well as in peripheral tissues. However, the neuronal function of APC is poorly understood. To investigate the functional role of Apc in the central nervous system, we analyzed the neurological phenotypes of Apc1638T/1638T mice, which carry a targeted deletion of the 3' terminal third of Apc that does not affect Wnt signaling.
A series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc1638T/1638T mice. Apc1638T/1638T mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc1638T/1638T mice showed abnormal dopamine and serotonin distribution in the brain. Some of these behavioral and neuronal phenotypes are related to symptoms and endophenotypes of schizophrenia.
Our results demonstrate that the C-terminus of the Apc tumor suppressor plays a critical role in cognitive and neuropsychiatric functioning. This finding suggests a potential functional link between the C-terminus of APC and pathologies of the central nervous system. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 11 | | Mol Genet Genomic Med 2015 Sep 3: 391-5 |
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| PMID | 26436104 |
| Title | Familial adenomatous polyposis in an adolescent with coexisting schizophrenia: treatment strategies and implications. |
| Abstract | Schizophrenia is associated with high mortality and morbidity. The etiology of schizophrenia remains unclear, studies implicate a multifactorial origin with genetic and environmental factors. The adenomatous polyposis coli (APC) gene has been associated with FAP (familial adenomatous polyposis), and studies have linked it to schizophrenia. However, there are few studies which examine the association between FAP and schizophrenia. Limited data exist regarding recommendations for genetic counseling of adolescents with comorbid psychiatric illness. A case of an adolescent with FAP who developed psychotic symptoms is presented. This case hopes to add to the literature about mental illness in those with FAP. A review of literature about the role of APC in schizophrenia as well as implications of genetic counseling on those who suffer with mental illness will be discussed. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 12 | | Schizophr. Res. 2015 Oct 168: 444-9 |
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| PMID | 26324334 |
| Title | Population-dependent contribution of the major histocompatibility complex region to schizophrenia susceptibility. |
| Abstract | There is consistent data from European cohorts suggesting a genetic contribution from the major histocompatibility complex (MHC) to the pathogenesis of schizophrenia. However, the genomic complexity and ethnicity-specific diversity found in the MHC cause difficulties in identifying causal variants or genes, and there is a need for studies encompassing the entire MHC region in multiple ethnic populations. Here, we report on association signals in the MHC region, with schizophrenia in the Japanese population. We genotyped and imputed a total of 10,131 single nucleotide polymorphisms (SNPs), spanning the entire MHC interval. The analysis included 3302 participants (1518 schizophrenics and 1784 healthy controls) from the Japanese population. In this study, we present evidence for association at rs494620, located in the SLC44A4 gene. The association survived after correction for multiple testing (unadjusted P=7.78×10(-5), empirical P=0.0357). The imputation results detected the highest association at rs707937 in the MSH5-SAPCD1 gene (imputed P=8.40×10(-5)). In expression analysis using postmortem brains from schizophrenia and control samples, MSH5-SAPCD1 showed marginally significant expression differences in Brodmann's area 46 (P=0.044 by unpaired t test with Welch's correction, P=0.099 by Mann-Whitney U test). Our study further strengthens evidence for the involvement of the MHC in schizophrenia across populations, and provides insight into population-specific mechanisms for the MHC region in schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 13 | | Schizophr. Res. 2015 Oct 168: 444-9 |
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| PMID | 26324334 |
| Title | Population-dependent contribution of the major histocompatibility complex region to schizophrenia susceptibility. |
| Abstract | There is consistent data from European cohorts suggesting a genetic contribution from the major histocompatibility complex (MHC) to the pathogenesis of schizophrenia. However, the genomic complexity and ethnicity-specific diversity found in the MHC cause difficulties in identifying causal variants or genes, and there is a need for studies encompassing the entire MHC region in multiple ethnic populations. Here, we report on association signals in the MHC region, with schizophrenia in the Japanese population. We genotyped and imputed a total of 10,131 single nucleotide polymorphisms (SNPs), spanning the entire MHC interval. The analysis included 3302 participants (1518 schizophrenics and 1784 healthy controls) from the Japanese population. In this study, we present evidence for association at rs494620, located in the SLC44A4 gene. The association survived after correction for multiple testing (unadjusted P=7.78×10(-5), empirical P=0.0357). The imputation results detected the highest association at rs707937 in the MSH5-SAPCD1 gene (imputed P=8.40×10(-5)). In expression analysis using postmortem brains from schizophrenia and control samples, MSH5-SAPCD1 showed marginally significant expression differences in Brodmann's area 46 (P=0.044 by unpaired t test with Welch's correction, P=0.099 by Mann-Whitney U test). Our study further strengthens evidence for the involvement of the MHC in schizophrenia across populations, and provides insight into population-specific mechanisms for the MHC region in schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
| 14 | | Neurosci Bull 2015 Oct 31: 617-25 |
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| PMID | 26253956 |
| Title | Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination. |
| Abstract | Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia. |
| SCZ Keywords | schizophrenia,schizophrenic,schizophrenics |
