RESUMEN

BACKGROUND: The number of patients with cognitive disorders is rapidly increasing in the world, becoming not only a medical problem, but also a social problem. There have been many reports that various factors are associated with cognitive dysfunction, but the factors have not yet been fully identified. This was a community-based complete enumeration study which aimed to identify risk and protective factors for dementia. METHODS: The first phase included all residents aged 65 years or older in a town in Japan. They completed many examinations, such as living conditions questionnaires, physical examination, Mini-Mental State Examination, and brain magnetic resonance imaging. The participants with suspected cognitive impairment underwent additional examinations for detailed evaluation in the second phase. Statistical analysis was performed to identify risk and protective factors for dementia after all participants were diagnosed. RESULTS: There were 927 participants in the baseline evaluation; 611 (65.9%) were healthy, 165 (17.8%) had mild cognitive impairment (MCI), and 151 (16.3%) had dementia. The age-standardised prevalence of dementia was 9.5%. Statistical analyses for amnestic MCI and Alzheimer's disease showed that risk factors for cognitive decline were diabetes mellitus, low activities of daily living, and living alone, and that protective factors were history of exercise and drinking habit. CONCLUSION: The present findings suggest that several lifestyle-related diseases and factors are associated with cognitive decline. These results support similar findings from previous studies and will be helpful for preventing dementia in the future.

Asunto(s)

RESUMEN

BACKGROUND: The onset of schizophrenia is associated with both genetic and environmental risks during brain development. Environmental factors during pregnancy can represent risk factors for schizophrenia, and we have previously reported that several microRNA and mRNA expression changes in fetal brains exposed to haloperidol during pregnancy may be related to the onset of this disease. This study aimed to replicate that research and focused on apoptotic-related gene expression changes. METHODS: Haloperidol (1 mg/kg) or aripiprazole (1 mg/kg) was injected into pregnant mice. Using RNA sequencing for the hippocampus of each offspring born from pregnant mice exposed to haloperidol, we analyzed genes identified as changed in our previous report and validated two apoptosis-related genes (Cdkn1a and Apaf1) using quantitative polymerase chain reaction (qPCR) methods. Furthermore, we attempted to elucidate the direct effects of haloperidol and aripiprazole on those mRNA expressions in in vitro experiments. RESULTS: RNA sequencing successfully replicated 16 up-regulated and 5 down-regulated genes in this study. Of those, up-regulations of Cdkn1a and Apaf1 mRNA expression were successfully validated by direct quantification. Moreover, haloperidol and aripiprazole dose-dependent upregulation of both mRNA expressions were confirmed in a Neuro2a cell line. CONCLUSIONS: In the hippocampus of offspring, intraperitoneal injection of haloperidol to pregnant mice induced up-regulation of apoptotic genes that representing the phenotypic change without apoptosis. These findings will be useful for understanding the molecular biological mechanisms underlying the effects of antipsychotics on the fetal brain.

Asunto(s)

RESUMEN

BACKGROUND: We explored the gene expression levels in the brain of 3xTg-AD model mice to elucidate the molecular pathological changes from the early to end stages of Alzheimer's disease (AD). OBJECTIVE: We re-analyzed our previously published microarray data obtained from the hippocampus of 3xTg-AD model mice at 12 and 52 weeks of age. METHODS: Functional annotation and network analyses of the up- and downregulated differentially expressed genes (DEGs) in mice aged 12 to 52 weeks were performed. Validation tests for gamma-aminobutyric acid (GABA)-related genes were also performed by quantitative polymerase chain reaction (qPCR). RESULTS: In total, 644 DEGs were upregulated and 624 DEGs were downregulated in the hippocampus of both the 12- and 52-week-old 3xTg-AD mice. In the functional analysis of the upregulated DEGs, 330 gene ontology biological process terms, including immune response, were found, and they interacted with each other in the network analysis. In the functional analysis of the downregulated DEGs, 90 biological process terms, including several terms related to membrane potential and synapse function, were found, and they also interacted with each other in the network analysis. In the qPCR validation test, significant downregulation was seen for Gabrg3 at the ages of 12 (p = 0.02) and 36 (p = 0.005) weeks, Gabbr1 at the age of 52 weeks (p = 0.001), and Gabrr2 at the age of 36 weeks (p = 0.02). CONCLUSION: Changes in immune response and GABAergic neurotransmission may occur in the brain of 3xTg mice from the early to end stages of AD.

Asunto(s)

RESUMEN

Aim: This study aimed to investigate the expression levels and methylation status of microtubule-associated protein tau (MAPT) in the blood of Alzheimer's disease (AD) patients and age- and sex-matched healthy controls. Methods: Fifty AD outpatients and 50 healthy contorls were enrolled. Blood samples were collected for processing of complementary DNA and genomic DNA. MAPT messenger ribonucleic acid (mRNA) expression was analyzed by real-time quantitative polymerase chain reaction. The methylation rates of four cytosine-phosphate-guanine (CpG) sites in the upstream region of MAPT exon1 were evaluated by the pyrosequencing method. Results: No significant differences in MAPT mRNA expression levels were found between AD and control subjects (AD 0.97 ± 0.49 vs. control 1.0 ± 0.64, p = 0.62). MAPT mRNA expression levels were not correlated with any other clinical characteristics or results of psychological tests. MAPT mRNA expression levels were significantly higher in AD subjects treated with acetylcholinesterase inhibitors (AchEIs) (n = 25) than in subjects not treated with AChEIs (n = 25) (unmedicated 0.83 ± 0.33 vs. medicated 1.12 ± 0.59, p = 0.049). The AD subjects did not differ from the control subjects in methylation rates at selected CpG sites. MAPT methylation status were not correlated with clinical characteristics, the results of psychological tests, or MAPT mRNA expression. Conclusion: MAPT mRNA expression levels and methylation status in blood do not appear useful as biomarkers for AD or the examined CpG sites were not genetically significant for MAPT gene expression or AD pathology. However, AChEIs may alter MAPT mRNA expression. Further studies are needed to explore blood biomarkers that can discriminate AD patients from controls.

RESUMEN

BACKGROUND: Cyclin-dependent kinase inhibitor 2A (CDKN2A) is an important gene in cellular senescence and aging. OBJECTIVE: This study assessed the utility of blood CDKN2A mRNA expression levels and methylation status as a potential biomarker for aging and the pathogenesis of Alzheimer's disease (AD). METHODS: The correlation between CDKN2A mRNA expression levels and age was examined in 45 healthy subjects, after which mRNA expression levels were compared among 46 AD patients, 20 mild cognitive impairment due to AD patients, 21 Parkinson's disease patients, 21 dementia with Lewy bodies patients, and 55 older healthy controls. The methylation rates of the second exon of the CDKN2A gene, known to influence its expression levels, was also examined. RESULTS: A significant correlation between CDKN2A mRNA expression levels and age was found (Spearman's rank correlation coefficient: r = 0.407, p = 0.005). CDKN2A mRNA expression levels in blood were significantly decreased in AD patients, although those of healthy controls were significantly increased with age. Further, only in AD patients were CDKN2A mRNA expression levels significantly and positively correlated with methylation rates. CONCLUSION: Although further research with a larger sample size is needed to elucidate the relationships between CDKN2A gene expression in blood and the development of other neurodegenerative diseases, CDKN2A mRNA expression in blood may be a biomarker for differentiating AD from normal aging and other neurodegenerative diseases.

Asunto(s)

RESUMEN

BACKGROUND: Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a validated genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with other neurodegenerative diseases. However, PICALM expression in the blood of neurodegenerative diseases remains elusive. OBJECTIVE: This study aimed to assess the usefulness of PICALM expression levels in the blood of patients with AD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and geriatric major depressive disorder (MDD) as a diagnostic biomarker. METHODS: In total, 45, 20, 21, and 19 patients with AD, PD, DLB, and geriatric MDD, respectively, and 54 healthy controls (HCs) were enrolled in the study. Expression data from Gene Expression Omnibus database (GSE97760), (GSE133347) and (GSE98793), (GSE48350), and (GSE144459) were used to validate the ability of biomarkers in the blood of patients with AD, PD, geriatric MDD, and a postmortem human AD brain and animal model of AD (3xTg-AD mouse), respectively. RESULTS: PICALM mRNA expression in human blood was significantly increased in patients with AD compared with that in HCs. PICALM mRNA expression and age were negatively correlated only in patients with AD. PICALM mRNA expression in human blood was significantly lower in patients with PD than in HCs. No changes in PICALM mRNA expression were found in patients with DLB and geriatric MDD. CONCLUSION: PICALM mRNA expression in blood was higher in patients with AD, but lower in patients with PD, which suggests that PICALM mRNA expression in human blood may be a useful biomarker for differentiating neurodegenerative diseases and geriatric MDD.

Asunto(s)

RESUMEN

The testing of pathological biomarkers of Alzheimer's disease (AD), such as amyloid beta and tau, is time-consuming, expensive, and invasive. Here, we used 3xTg-AD mice to identify and validate putative novel blood transcriptome biomarkers of AD that can potentially be identified in the blood of patients. mRNA was extracted from the blood and hippocampus of 3xTg-AD and control mice at different ages and used for microarray analysis. Network and functional analyses revealed that the differentially expressed genes between AD and control mice modulated the immune and neuroinflammation systems. Five novel gene transcripts (Cdkn2a, Apobec3, Magi2, Parp3, and Cass4) showed significant increases with age, and their expression in the blood was collated with that in the hippocampus only in AD mice. We further assessed previously identified candidate biomarker genes. The expression of Trem1 and Trem2 in both the blood and brain was significantly increased with age. Decreased Tomm40 and increased Pink1 mRNA levels were observed in the mouse blood. The changes in the expression of Snca and Apoe mRNA in the mouse blood and brain were similar to those found in human AD blood. Our results demonstrated that the immune and neuroinflammatory system is involved in the pathophysiologies of aging and AD and that the blood transcriptome might be useful as a biomarker of AD.

Asunto(s)

RESUMEN

CTL-associated antigen 4 (CTLA4) and its downstream signals compose an important mechanism that suppresses immune activity. Recent studies have shown that immune abnormalities are associated with the pathogenesis of schizophrenia (SCZ), but little research has been performed on the relevance of CTLA4 and SCZ. In the present study, we investigated the relationship between CTLA4 mRNA expression and SCZ. We examined the expression of CTLA4 mRNA in blood from patients with SCZ, bipolar disorder (BD), and major depressive disorder (MDD). We compared 50 SCZ subjects, 46 BD subjects, and 63 MDD subjects with age- and sex-matched healthy controls (HCs). Quantitative real-time PCR was performed to examine CTLA4 mRNA expression in peripheral blood using TaqMan probes. Levels of CTLA4 mRNA expression were significantly lower in patients with SCZ compared with HCs (p < 0.001), whereas no differences were found between affective disorder (BD and MDD) patients and HCs. We analyzed the correlation between CTLA4 mRNA expression and clinical parameters, but no significant correlation was found. The expression of CTLA4 mRNA was lower specifically in SCZ, suggesting that abnormal CTLA4 expression may be particularly related to the pathogenesis of SCZ. CTLA4 may be a useful diagnostic marker and a potential therapeutic target of SCZ.

Asunto(s)

RESUMEN

INTRODUCTION: Although ATP-binding cassette sub-family A member 7 gene (ABCA7) is known to be associated with Alzheimer's disease, the relationship between ABCA7 and schizophrenia has been unknown. METHODS: Schizophrenia patients (n = 50; 24 males, 62.1 ± 0.50 years old) and age- and sex-matched healthy controls (n = 50) were recruited for the mRNA analysis. Additionally, a case-control study for the rs3764650 genotypes was performed with 1308 samples (control subjects; n = 527, schizophrenia patients; n = 781). All participants were Japanese, unrelated to each other, and living in the same area. RESULTS: The distributions of the rs3764650 genotypes in schizophrenia patients were not different from that of controls. However, the ABCA7 mRNA expression levels in schizophrenia patients were significantly higher than those in controls by a logistic regression analysis. Additionally, the ABCA7 mRNA expression levels in schizophrenia patients were correlated with the rs3764650 genotypes in a dose-dependent manner. DISCUSSION: The ABCA7 mRNA expression levels in peripheral blood with the rs3764650 genotypes may be related to pathological mechanisms in schizophrenia and may be a biological marker for schizophrenia.

RESUMEN

OBJECTIVE: The aim was to clarify whether DRD2 methylation changes in leukocytes of dementia with Lewy bodies (DLB) or Parkinson's disease (PD) patients are seen and can be used to discriminate between them. METHODS: Methylation rates were examined in 23 DLB subjects and 23 age- and sex-matched healthy controls and 37 PD patients and 37 age- and sex-matched healthy controls. RESULTS: Significant DRD2 DNA methylation changes were found in leukocytes of DLB and PD patients compared with healthy subjects. Discriminant analysis between DLB and PD using seven CpG sites demonstrated sensitivity and specificity of 83.8% and 90.9%, respectively. None of the CpG sites were associated with sex, age, age of onset, disease duration, and any of the neuropsychological tests in DLB and PD patients. CONCLUSION: This is the first report showing that DRD2 DNA methylation rates in leukocytes were increased in DLB patients and decreased in PD patients. These results may be an important step in understanding epigenetic mechanisms underlying DLB and PD pathogenesis and providing a novel biomarker for discriminating between them.

Asunto(s)

RESUMEN

The gene for dopamine receptor D2 (DRD2) is associated with schizophrenia (SCZ). Epigenetic changes may be related to SCZ pathology. The -141C Ins/Del polymorphism in DRD2 (rs1799732) is functional and associated with SCZ. Fifty SCZ patients and 50 control subjects were newly recruited and analyzed in addition to 50 previously reported SCZ samples and 50 previously reported control samples. Genomic DNA from peripheral leukocytes was analyzed. We replicated analysis of DNA methylation rates at seven CpG sites (CpG 1-1 to 1-7) and also analyzed five additional sites (CpG 2-1 to 2-5) in the upstream region of DRD2. We also performed genotyping of -141C IIns/Del and analyzed the effects of -141C Ins/Del on methylation of DRD2. Methylation rates were significantly lower in SCZ patients compared to control subjects, respectively. In control subjects, the methylation rates were significantly lower in individuals with the Ins/Ins genotype than in Del allele carriers. We replicated hypomethylation of the DRD2 promoter region in SCZ patients compared to age-matched control subjects. The -141C Ins/Del polymorphism affected the methylation rates in regions of DRD2. Hypomethylation and the -141C Ins/Del polymorphism of DRD2 may be biomarkers for SCZ.

Asunto(s)

RESUMEN

OBJECTIVES: Ghrelin regulates appetite and also plays important roles in cognition and may be involved in vulnerability to SCZ. METHODS: In this study, we measured mRNA expression of the ghrelin-related molecules, growth hormone secretagogue receptor 1a (GHS-R1a) and 1b (GHS-R1b), and the ghrelin activator, membrane bound O-acyltransferase 4 (MBOAT4). Peripheral leukocytes from Japanese patients with SCZ (n = 49; 23 males, 26 females; age = 61.8 ±â€¯13.3 years) and controls (n = 50; 25 males, 25 females; age = 62.0 ±â€¯14.3 years) were recruited according to their clinical information. We also studied the DNA methylation rates of these genes in DNA from leukocytes. RESULTS: The mRNA expression of GHS-R1a was significantly decreased in SCZ (SCZ vs. control: 0.35 ±â€¯0.081 vs. 1.00 ±â€¯0.059, respectively, p = 0.007), but expression levels of GHS-R1b and MBOAT4 were significantly increased in SCZ (SCZ vs. control: 2.02 ±â€¯0.91 vs. 1.00 ±â€¯0.32, p = 0.023, 1.37 ±â€¯0.21 vs. 1.00 ±â€¯0.11, respectively, p = 0.014). No differences in methylation rates for any genes were found. CONCLUSION: We conclude that opposite expression of GHS-R1a and GHS-R1b, and elevated MBOAT4 mRNA expression may reflect the mechanisms of SCZ.

Asunto(s)

RESUMEN

The neuroprotective effect of ghrelin has recently been reported in Alzheimer's disease (AD). Ghrelin is converted from des-acyl ghrelin to the activated form, acyl ghrelin, by membrane bound o-acyltransferase 4 (MBOAT4), and then binds to growth hormone secretagogue receptor (GHS-R). We examined the levels of plasma acyl/des-acyl ghrelin in 75 AD subjects and age- and sex-matched controls, as well as the DNA methylation and mRNA expression of MBOAT4 and GHS-R in peripheral leukocytes. The acyl ghrelin concentration was significantly higher in AD subjects than in controls (2.18 ±â€¯1.25 vs. 1.49 ±â€¯2.3, p = 0.001). The methylation rate of MBOAT4 CpG 2 was significantly lower in AD subjects than in controls (4.0 ±â€¯0.9 vs. 4.7 ±â€¯1.2, p < 0.001). The mRNA expression levels of MBOAT4 and GHS-R1b were significantly higher in AD subjects than in controls (MBOAT4: 1.10 ±â€¯0.48 vs. 1.0 ±â€¯0.55, p = 0.049; GHS-R1b: 1.76 ±â€¯3.18 vs. 1.0 ±â€¯1.56, p = 0.030). These changes in the ghrelin cascade in peripheral blood may reflect those in the brain, and may be a neuroprotective biomarker in AD.

Asunto(s)

RESUMEN

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) activates the innate immune system, promotes phagocytosis by microglia, and is associated with Alzheimer's disease (AD). The possible role of a related molecule, TREM1, in AD remains unknown. OBJECTIVE: We investigated a possible role for TREM1 in AD by determining the gene expression and methylation levels of TREM1 in leukocytes from AD patients. METHODS: Fifty patients with AD and 50 age-matched healthy controls were enrolled. AD patients underwent a battery of neuropsychiatric tests. Peripheral blood samples were obtained from each participant, RNA and DNA were extracted, and samples were assessed for TREM1 mRNA expression and methylation rates at three CpG sites in the TREM1 promoter. RESULTS: TREM1 mRNA expression levels in AD patients were significantly higher than those in controls (p = 0.008). TREM1 mRNA expression levels were not correlated with sex, age, duration of illness, APOE genotype, donepezil treatment, or scores of most neuropsychiatric tests. TREM1 mRNA expression levels in AD patients were correlated with the total score of the Montgomery-Åsberg Depression Rating Scale (p = 0.047, r = - 0.344). Methylation rates at the three CpG sites were significantly lower in AD patients than in controls. We also found a significant correlation between TREM1 mRNA expression and TREM1 DNA methylation rates (p < 0.001). CONCLUSION: TREM1 may be associated with the immune responses in AD, and along with hypomethylation at CpG sites in the TREM1 promoter, may become part of a biomarker panel for AD pathogenesis.

Asunto(s)

RESUMEN

AIM: Despite continuing research into Alzheimer's disease (AD), its pathological mechanisms and modulating factors remain unknown. Several genes influence AD pathogenesis by affecting inflammatory pathways. Myocyte-enhancer factor 2C (MEF2C) is one such candidate gene for AD. METHODS: We examined MEF2C mRNA expression levels and methylation rates of CpG on its promoter region in peripheral leukocytes from Japanese AD patients compared with age- and sex-matched control subjects. RESULTS: In peripheral leukocytes, MEF2C mRNA expression levels in AD subjects were significantly lower than those in control subjects (0.86 ± 0.25 vs 0.99 ± 0.27, respectively, P = 0.007) and were correlated with the Alzheimer's Disease Assessment Scale (r = -0.345, P = 0.049) and the Mini Mental State Examination (r = 0.324, P = 0.02). No significant differences were found in methylation rates between AD and control subjects. CONCLUSION: MEF2C mRNA expression in leukocytes may be a biological marker for cognitive decline in AD.

Asunto(s)

RESUMEN

The clinical features in cases that have mutations in the microtubule-associated protein tau gene but lack prominent behavioral changes remain unclear. Here, we describe detailed clinical and pathological features of a case carrying the P301L tau mutation that showed only apathy until the middle stage of the course. The mother of this case was suspected to have mild cognitive decline at age 46. However, before she was fully examined, she had a subarachnoid hemorrhage at age 49 and died at age 53. An autopsy was not done. The proband of this pedigree, a 60-year-old right-handed Japanese man at the time of death, began to make mistakes at work at the age of 51 years. Until age 54, he showed only mild apathy with bradykinesia. Insight was well spared. Parkinsonism and echolalia developed at age 55, and pyramidal signs and oral tendency at age 57. Personality change, disinhibition, stereotypy, or semantic memory impairment was not found throughout the course. The final neurological diagnosis was unspecified dementia. Pathological examination demonstrated numerous round four-repeat tau-positive three-repeat tau-negative or perinuclear ring-like neuronal cytoplasmic inclusions with many ballooned neurons in the frontal and temporal cortices and hippocampus. Genetic analysis using frozen brain tissue demonstrated a P301L tau mutation. Among 31 previously reported cases bearing the P301L tau mutation for which the data regarding initial symptoms are available, one clinical case showed only apathy with depression in the early stage. Given these findings, clinicians should be aware that a clinical course characterized only by apathy for several years, which can be misdiagnosed as a psychiatric disorder, is one of the clinical presentations associated with P301L tau mutation.

Asunto(s)

RESUMEN

BACKGROUND: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE), andis reported in several genome-wide association studies to be associated with Alzheimer's disease (AD). OBJECTIVE: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD. METHODS: We examined TOMM40, PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PARK2), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40exon 1 in peripheral leukocytes and TOMM40523 polyT genotypes in 60 AD and age- and sex-matched control subjects. RESULTS: TOMM40 mRNA expression was significantly lower in AD subjects (0.87±0.18 versus 1.0±0.23, p = 0.005), and PINK1 mRNA expression was higher in AD subjects (1.5±0.61 versus 1.0±0.52, p < 0.001). TOMM40 mRNA expression was significantly correlated with the Mini-Mental State Examination total score (r = 0.290, p = 0.027). There was no expressional change in peripheral APOE mRNA in either AD or control subjects (p = 0.32). Methylation rates in the upstream region of TOMM40exon 1 were not different between AD and control subjects (average rate: 1.37±0.99 versus 1.39±1.20, p = 0.885), and TOMM40523 polyT genotypes were also not different between AD and control subjects (p = 0.67). CONCLUSION: TOMM40 mRNA expression was lower in AD subjects and was correlated with cognitive decline. Significant changes in both TOMM40 and PINK1 mRNA may be related to mitochondrial dysfunction.

Asunto(s)

RESUMEN

It is very rare that cases of Pick's disease, a representative three-repeat (3R) tauopathy, also have significant four-repeat (4R) tau accumulation. Here, we report a Pick's disease case that clinically showed behavioral variant frontotemporal dementia without motor disturbance during the course, and pathologically had 3R tau-positive Pick bodies as well as numerous 4R tau-positive neuronal cytoplasmic inclusions (NCIs). Abundant 3R tau-positive 4R tau-negative spherical or horseshoe-shaped Pick bodies were found in the frontotemporal cortex, limbic region, striatum and pontine nucleus. On the other hand, many 4R tau-positive, 3R tau-negative, Gallyas-negative dot-, rod- or intertwined skein-like NCIs were found mainly in the subthalamic nucleus, pontine nucleus, inferior olivary nucleus and cerebellar dentate nucleus. Tufted astrocytes, astrocytic plaques, argyrophilic grains or globular glial inclusions were absent. Double-labeling immunofluorescence demonstrated that 3R tau was hardly accumulated in 4R tau-positive inclusions. On tau immunoblotting, while 60 and 64 kDa bands were demonstrated in the frontal cortex, 60, 64 and 68 kDa bands, as well as the 33 kDa tau fragments that are reported to be characteristic of progressive supranuclear palsy brains, were found in the basal ganglia and cerebellum. No mutation was identified in the tau gene. The present case suggests that, although probably rare, some Pick's disease cases have non-negligible 4R tau pathology in the subcortical nuclei, and that such 4R tau pathology can affect the evaluation of the distribution of AT8-positive tau pathology in Pick's disease cases.

Asunto(s)

RESUMEN

A hypothesis for schizophrenia (SCZ) called the "microglia hypothesis" has been suggested. In SCZ, expression of triggering receptor expressed on myeloid cell 2 (TREM2) mRNA is higher in leukocytes than in healthy individuals. Here, the methylation rates of four CpG sites in TREM2 intron 1 that may bind important transcription factors and the correlation between the methylation rate and mRNA expression were determined. We compared the methylation rates in SCZ patients and age-matched controls (n = 50 each). SCZ patients had significantly lower methylation rates of CpG 2 (17.0 ± 6.7 vs. 20.2 ± 5.0; p = 0.02) and CpG 3 (23.8 ± 8.2 vs. 28.1 ± 6.2; p = 0.01). The average methylation rate (15.3 ± 5.2 vs. 17.6 ± 3.9; p = 0.009) was also lower. A significant negative correlation was found between TREM2 mRNA expression and the methylation rate of CpG 2 (r = -0.252, p = 0.012). SCZ susceptibility markers may include low methylation at TREM2 intron 1 and increased TREM2 mRNA levels. Our pilot study requires validation with higher numbers of participants and with other myeloid cell types.

RESUMEN

Microglial dysfunction and inflammation have recently been shown to be related to the development of Alzheimer's disease (AD). Inositol polyphosphate-5-phosphatase (INPP5D) functions broadly as a negative regulator of immune signaling, and its locus was associated with development of AD in a large-scale genome-wide association study. Thus, we examined INPP5D mRNA expression and methylation rates of the CpG sites in the upstream region of INPP5D exon 1 in peripheral leukocytes in 50 AD and age- and sex-matched control subjects. INPP5D mRNA expression in AD subjects was significantly higher than that in control subjects (1.16±0.39 versus 1.0±0.23, p = 0.049) and was correlated with the Mini-Mental State Examination score (p = 0.002, r = 0.426) and the total score of the Alzheimer's Disease Assessment Scale (p < 0.001, r = -0.697). Methylation rates in the upstream region of INPP5D exon 1 were not significantly different between AD and control subjects (average rate: 3.5±3.0 versus 2.8±1.3, p = 0.551). Our results suggested that INPP5D mRNA expression was elevated in the early stage and decreased with cognitive decline in AD. INPP5D mRNA expression in leukocytes may be a useful biomarker for the early stage of AD.

Asunto(s)