Search PubMed⌕ Search

Biomedical subjects

Masatoshi Takeda

Publications and source records attributed to Masatoshi Takeda.

At least 37 records · Page 2Linked to original sources
PubMed2005

A novel alternative splice variant of nicastrin and its implication in Alzheimer disease.

Nicastrin interacts with gamma-secretase complex components predominantly via the N-terminal third of the transmembrane domain. The authentic transmembrane domain is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex. In this study, we have identified a novel alternatively spliced transcript of nicastrin in human brain tissue. This transcript (NCSTN-DeltaE16) lacks exon 16 of nicastrin mRNA, which leads to deletion of 71 amino acids just upstream of its transmembrane domain. Its expression pattern was analyzed in the hippocampus of patients with pathologically diagnosed Alzheimer disease (cases) and non-Alzheimer dementia (controls). In patients with the APOE-epsilon4 allele, the frequency of Alzheimer disease appeared to be increased in the NCSTN-DeltaE16-positive group, but the association was not statistically significant. In conclusion, the expression of NCSTN-DeltaE16 transcript may confer some additional risk for developing Alzheimer disease beyond the risk due to ApoE-epsilon4 allele. Further investigation in larger scale population would be necessary to address its potential implication in Alzheimer disease.

Age of Onset↗
PubMed2005

Lymphocyte-specific protein tyrosine kinase is a novel risk gene for Alzheimer disease.

Lymphocyte-specific protein tyrosine kinase (LCK) is a lymphoid-specific, Src family protein tyrosine kinase that is known to play a pivotal role in T-cell activation and interact with the T-cell coreceptors, CD4 and CD8. It has been shown to be significantly down-regulated in Alzheimer disease (AD) hippocampus compared with non-demented controls. Furthermore, it is located in a previously identified genetic linkage region (1p34-36) associated with AD. Therefore, we consider it to be a candidate gene for AD. We examined the relationship between AD and the LCK and apolipoprotein E (APOE) genes in 376 AD (including 323 late-onset AD (LOAD) cases and 53 early-onset AD (EOAD) cases) and 378 non-demented controls using a single nucleotide polymorphism (SNP). The polymorphism in intron 1 (+6424 A/G) was significantly associated with AD risk. The odds ratio (OR) for total AD associated with the GG genotype was 1.41 (95% CI=1.06-1.87) and that for LOAD was 1.37 (95%CI=1.02-1.85), while that for APOE-epsilon4 was 5.06 (95% CI=3.60-7.12). In the APOE-epsilon4 non-carrier subgroup, the GG genotype also showed significant association (OR=1.66; 95% CI=1.16-2.38). These results indicate that the LCK is a novel risk gene for AD regardless of the APOE genotype.

Age of Onset↗
PubMed2005

Association between cognitive impairment and gait disturbance in patients with idiopathic normal pressure hydrocephalus.

We compared the scores of the Frontal Assessment Battery (FAB), initial fluency subtest, category fluency subtest and subtests of the Mini-Mental State Examination (MMSE) between patients with idiopathic normal pressure hydrocephalus (iNPH) and age-, sex- and MMSE-matched patients with Alzheimer's disease (AD). In patients with iNPH, the time and number of steps required to go and come back a 10-meter distance were measured (Walking test) and the associations between the scores of the cognitive tests and the performance of the Walking test were evaluated. The scores of the FAB and initial fluency subtest in patients with iNPH were significantly lower than those in patients with AD. The scores of the FAB, initial fluency subtest and serial 7 subtest of the MMSE significantly correlated with the two scores of the Walking test in patients with iNPH. The present results indicate that frontal lobe functions were impaired in patients with iNPH and that cognitive impairment was closely associated with gait disturbance in patients with iNPH.

Aged↗
PubMed2005

Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2.

Presenilins 1 and 2 (PS1/2), causative molecules for familial Alzheimer's disease (FAD), are multipass transmembrane proteins localized predominantly in the endoplasmic reticulum (ER) and Golgi apparatus. Heteromeric protein complexes containing PS1/2 are thought to participate in several functions, including intramembrane proteolysis mediated by their gamma-secretase activities. Previous studies have shown that PS1/2 are also involved in the regulation of apoptotic cell death, although the underlying mechanism remains unknown. Here, we demonstrate that FKBP38, an immunophilin family member residing in the mitochondrial membrane, is an authentic PS1/2-interacting protein. PS1/2 and FKBP38 form macromolecular complexes together with anti-apoptotic Bcl-2. PS1/2 promote the degradation of FKBP38 and Bcl-2 and sequester these proteins in the ER/Golgi compartments, thereby inhibiting FKBP38-mediated mitochondrial targeting of Bcl-2 via a gamma-secretase-independent mechanism. Thus, PS1/2 increase the susceptibility to apoptosis by antagonizing the anti-apoptotic function of FKBP38. In contrast, C-terminal fragments of caspase-processed PS1/2 redistribute Bcl-2 to the mitochondria by abrogating the activity of full-length PS1/2, resulting in a dominant-negative anti-apoptotic effect. In cultured cells and mutant PS1-knockin mice brains, FAD-linked PS1/2 mutants enhance the pro-apoptotic activity by causing a more efficient reduction in mitochondrial Bcl-2 than wild-type PS1/2. These results suggest a novel molecular mechanism for the regulation of mitochondria-mediated apoptosis by competition between PS1/2 and FKBP38 for subcellular targeting of Bcl-2. Excessive pro-apoptotic activity of PS1/2 may play a role in the pathogenesis of FAD.

Alzheimer Disease↗
PubMed2005

Information processing flow and neural activations in the dorsolateral prefrontal cortex in the Stroop task in schizophrenic patients. A spatially filtered MEG analysis with high temporal and spatial resolution.

Using a spatially filtered magnetoencephalography analysis (synthetic aperture magnetometry), we estimated neural activations in the Stroop task in nearly real time for schizophrenic patients with/without auditory hallucinations and for normal control subjects. In addition, auditory hallucinations were examined through the information processing flow of the brain neural network, including the frontal regions. One hundred unaveraged magnetoencephalography signals during the incongruent stimulus responses were analyzed with a time window of 200 ms in steps of 50 ms. In the 25-60-Hz band, cortical regions that showed significant current source density changes were examined for each time window. The three groups showed significantly decreased current source density, corresponding to neural activation, with temporal overlap along the fundamental cognitive information processing flow: sensory input system, executive control system, motor output system. Transient neural activations in the dorsolateral prefrontal cortex were bilateral with left-side dominancy for normal controls, left-lateralized for nonhallucinators and right-lateralized for hallucinators. Our results suggest that the dysfunction in the left dorsolateral prefrontal cortex was related to auditory hallucinations, while the information processing flow was unaffected in the schizophrenic subjects in the Stroop task.

Adolescent↗
PubMed2005

Everyday memory impairment of patients with mild cognitive impairment.

We evaluated everyday memory impairment in 24 patients with mild cognitive impairment (MCI) with the Rivermead Behavioral Memory Test (RBMT) and compared the scores with those of 48 age-, sex- and education-matched normal controls (NC) and 48 age-, sex- and education-matched Alzheimer disease (AD) patients. Overall everyday memory was impaired in MCI patients but the severity was milder than that in AD patients. The MCI patients showed impairment of everyday memory tasks requiring delayed recall. But they could normally perform tasks immediately after memorizing, except for recalling and retracing a simple new route. The total Profile score correctly classified 100% of the MCI patients and 91.7% of NC, thus demonstrating the usefulness of the RBMT for diagnosing MCI patients. Prospective memory tasks were not useful for detecting the patients with MCI.

Aged↗
PubMed2005

Identification of hippocampus-related candidate genes for Alzheimer's disease.

Alzheimer's disease (AD) is a complex multifactorial disease in which many genetic and environmental factors are involved. We performed an association study using 376 AD patients and 376 control subjects. We studied 35 single nucleotide polymorphisms in 35 genes that were significantly downregulated or upregulated only in the AD hippocampus compared with control and found that 9 single nucleotide polymorphisms were associated with AD. Our data indicated that single nucleotide polymorphisms could highly reflect differences in gene expression. Furthermore, an intronic polymorphism (+9943T/C) in POU2F1 was most significantly associated with AD (p = 0.0007). Our results suggest that POU2F1 is a candidate gene for AD.

Aged↗
PubMed2005

Neptune is involved in posterior axis and tail formation in Xenopus embryogenesis.

In order to elucidate the molecular mechanisms underlying the posterior axis and tail formation in embryogenesis, the function of Neptune, a zinc-finger transcription factor, in Xenopus laevis embryos was investigated. Injection of neptune mRNA into the animal pole area of embryos resulted in the formation of an additional tail structure that included a neural tube and muscle tissue. This activity required FGF signaling since coinjection of a dominant-negative FGF receptor RNA (XFD) completely blocked the formation of a tail structure. A loss-of-function experiment using a fusion construct of neptune and Drosophila engrailed (en-neptune) RNA showed that endogenous Neptune is necessary for formation of the posterior trunk and tail. Furthermore, activity of Neptune was necessary for the endogenous expression of brachyury and fgf-8 at the late gastrula stage. These findings demonstrate a novel function of Neptune in the process of anterior-posterior axis formation through the FGF and brachyury signaling cascades. An experiment using a combination explant with ventral and dorsal marginal tissues showed that cooperation of these two distinct tissues is important for the tail formation and that expression of Neptune in prospective ventral cells may be involved in the activation of the process of tail formation.

Animals↗
PubMed2005

A stress-induced, superoxide-mediated caspase-1 activation pathway causes plasma IL-18 upregulation.

Psychological/physical stresses are known to cause relapses of autoimmune and inflammatory diseases. To reveal a mechanism by which noninflammatory stresses affect host defenses, responses to immobilization stress in mice were investigated, focusing on the role of a multifunctional cytokine, interleukin-18 (IL-18). In the adrenal cortex, the stress induced IL-18 precursor proteins (pro-IL-18) via adrenocorticotropic hormone (ACTH) and a superoxide-mediated caspase-1 activation pathway, resulting in conversion of pro-IL-18 to the mature form, which was released into plasma. Inhibitors of caspase-1, reactive oxygen species, and P38 mitogen-activated protein kinase (MAPK) suppressed stress-induced accumulation of plasma IL-18. These inhibitors also blocked stress-induced IL-6 expression. This, together with the observation that IL-6 was not induced in IL-18-deficient mice, showed that IL-6 induction by stress is dependent on IL-18. In stressed organisms, IL-18 may influence pathological and physiological processes. Controlling the caspase-1 activating pathway to suppress IL-18 levels may provide preventative means against stress-related disruption of host defenses.

Adrenal Cortex↗
PubMed2005

Event-related potentials in panic disorder and generalized anxiety disorder.

To evaluate the neurophysiological differences between panic disorder (PD) and generalized anxiety disorder (GAD), 52 patients with PD and 34 with GAD were investigated using event-related potentials (ERP). The ERP were recorded using a tone discrimination task, and peak latencies for N1, P2, N2, and P3 at a Pz electrode site were measured. In addition to analyzing the peak latencies of the ERP, the interpeak latencies (IPL; N1-P2, P2-N2, and N2-P3) were also analyzed. The same analysis was performed in 28 age-matched healthy volunteers (controls). When compared to those of the GAD and control groups, the mean latencies of P2, N2, and P3 were shorter in the PD patients. With regard to the IPL in the PD patients, the N1-P2 IPL was shorter than that in the other groups, and no individual with PD had a longer N1-P2 IPL than 1 SD above the mean of the controls. These findings suggest that certain attention-related processes in the cerebrum that affect ERP data are accelerated in PD patients. These findings demonstrate that it may be useful to neurophysiologically distinguish PD from GAD by measuring ERP peak latencies and IPL.

Adolescent↗
PubMed2005

Prediction of first episode of panic attack among white-collar workers.

The purpose of the present study was to elucidate a longitudinal matrix of the etiology for first-episode panic attack among white-collar workers. A path model was designed for this purpose. A 5-year, open-cohort study was carried out in a Japanese company. To evaluate the risk factors associated with the onset of a first episode of panic attack, the odds ratios of a new episode of panic attack were calculated by logistic regression. The path model contained five predictor variables: gender difference, overprotection, neuroticism, lifetime history of major depression, and recent stressful life events. The logistic regression analysis indicated that a person with a lifetime history of major depression and recent stressful life events had a fivefold and a threefold higher risk of panic attacks at follow up, respectively. The path model for the prediction of a first episode of panic attack fitted the data well. However, this model presented low accountability for the variance in the ultimate dependent variables, the first episode of panic attack. Three predictors (neuroticism, lifetime history of major depression, and recent stressful life events) had a direct effect on the risk for a first episode of panic attack, whereas gender difference and overprotection had no direct effect. The present model could not fully predict first episodes of panic attack in white-collar workers. To make a path model for the prediction of the first episode of panic attack, other strong predictor variables, which were not surveyed in the present study, are needed. It is suggested that genetic variables are among the other strong predictor variables. A new path model containing genetic variables (e.g. family history etc.) will be needed to predict the first episode of panic attack.

Adult↗
PubMed2005

Neural basis of fear conditioning induced by video clip: positron emission tomography study.

In patients with post-traumatic stress disorder (PTSD), re-experiencing the trauma is often induced by external cues in the environment. The cues, which were emotionally neutral for the patients before the traumatic event, become fearful ones after the event. This phenomenon is considered to be associated with fear conditioning. The paradigm was set up so that the emotionality changes in the patients with PTSD would be reproduced, and the regional cerebral blood flow (rCBF) measured with positron emission tomography (PET) was compared during exposure to the same stimuli before and after acquisition of fear conditioning. Ten healthy male subjects were asked to look at some emotionally neutral photos, then to watch a video with fearful content that also contained images similar to that presented in the photos, and afterwards to look at the photos again. Five of the 10 subjects felt that the object in the photos was more fearful after watching the video than before, and they were considered to have acquired fear conditioning. In those five subjects, the rCBF in the right amygdala and the left posterior cingulate gyrus after acquisition of fear conditioning significantly increased relative to the rCBF before conditioning. Thus, these regions seem to have a critical role in fear conditioning.

Adult↗
PubMed2005

Spatial working memory deficit correlates with disorganization symptoms and social functioning in schizophrenia.

Both spatial working memory deficit and disorganization symptoms have been considered significant components of schizophrenic impairment involved with the dorsolateral prefrontal cortex. The purpose of the present study was to investigate the relationships among spatial working memory, psychiatric symptoms including disorganization symptoms, and social functioning in schizophrenia. Fifty clinically stable patients with schizophrenia and 34 healthy controls participated in the study. Patients were rated with the Brief Psychiatric Rating Scale and the Rehabilitation Evaluation Hall and Baker. The Advanced Trail Making Test was used to evaluate spatial working memory. Patients demonstrated significantly reduced spatial working memory compared to that of healthy controls. Spatial working memory in patients correlated significantly with social functioning such as self-care skills, community skills and speech disturbance, and with disorganization symptoms. Disorganization symptoms also correlated with these aspects of social functioning. In conclusion it is suggested that both spatial working memory deficit and disorganization symptoms, which are impairments involved with the dorsolateral prefrontal cortex dysfunction, can serve as effective predictors of social functioning.

Adult↗
PubMed2005

Detection by radioligand assay of antibodies against Borna disease virus in patients with various psychiatric disorders.

Using a radioligand assay, which preserves the natural form of the antigen, antibodies against Borna disease virus nucleoprotein and phosphoprotein were detected in 11 and 19 sera of 171 psychiatric patients, respectively. Compared with results by Western blotting, three and nine sera were concordantly positive, respectively. The four sera showing the highest levels of antibodies by radioligand assay were all negative by Western blotting; however, dilution and inhibition tests supported the positive results. Our results suggest the importance of conformational structure to detect human anti-Borna disease virus antibodies.

Antibodies, Viral↗
PubMed2005

Molecular genetics of Alzheimer's disease and aging.

Alzheimer's disease is a genetically complex disorder associated with multiple genetic defects, either mutational or of susceptibility. Although potentially associated with an accelerated stochastically driven aging process, Alzheimer's disease is an independent clinical entity in which the aging process exerts a deleterious effect on brain activity in conjunction with polymodal genetic factors and other pathological conditions (i.e., age-related cerebrovascular deterioration) and environmental factors (i.e., nutrition). Alzheimer's disease genetics does not explain in full the etiopathogenesis of this disease. Therefore, it is likely that environmental factors and/or epigenetic phenomena also contribute to Alzheimer's disease pathology and phenotypic expression of dementia. The genomics of Alzheimer's disease is still in its infancy, but this field is aiding the understanding of novel aspects of this disease, including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically regulated metabolic cascades. Alzheimer's disease genomics is also helping to develop new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerate drug development for Alzheimer's disease and other complex disorders. The multifactorial genetic dysfunction in dementia includes mutational loci (APP, PS1, PS2, TAU) and diverse susceptibility loci (APOE, alpha2M, alphaACT, LRP1, IL1 alpha, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3 beta, NOS3 and many other genes) distributed across the human genome, probably converging in a common pathogenic mechanism that leads to premature neuronal death, in which mitochondrial DNA mutations may contribute to increased genetic variability and heterogeneity. In Alzheimer's disease, multiple pathogenic events, including genetic factors, accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, excitotoxic reactions, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis, dysfunction of axonal and dendritic transport, and chaperone misoperation may converge in pathogenic pathways leading to premature death and neurodegeneration. Some of these mechanisms are common to several neurodegenerative disorders, which differ depending upon the gene(s) affected and the involvement of specific genetic networks, together with epigenetic factors and environmental events. Many genes potentially associated with Alzheimer's disease in some studies cannot be confirmed as candidate genes in replication studies, indicating that methodological problems and genomic complexity are leading to erroneous conclusions. A different approach to Alzheimer's disease functional genomics is to integrate individual genetic information in polygenic genotypes (haplotype-like model) and to investigate genotype-phenotype correlations and genotype-related pharmacogenomic behaviors. The application of functional genomics to Alzheimer's disease can be a suitable strategy for molecular diagnosis and for understanding pathophysiological mechanisms associated with Alzheimer's disease-related neurodegeneration. Furthermore, the pharmacogenomics of Alzheimer's disease may contribute in the future to optimize drug development and therapeutics, increasing efficacy and safety, and reducing side-effects and unnecessary costs.

Aging↗
PubMed2004

Amyloid-beta down-regulates XIAP expression in human SH-SY5Y neuroblastoma cells.

Recent observations suggest that amyloid-beta (Abeta), a major constituent of senile plaques, induces apoptosis in cultured neuronal cells. However, the concentration of Abeta that leads to neuronal cell death is much higher (10-25 microM) than that in the cerebrospinal fluid of normal controls or AD patients (nM order). As reported here, we found that subtoxic concentrations (100-500 nM) of Abeta(1-42) can down-regulate the expression of the X-linked inhibitor of apoptosis (XIAP) in human SH-SY5Y neuroblastoma cells, and that vulnerability to oxidative stress caused by Abeta(1-42) is attenuated by over-expression of XIAP. These results suggest that down-regulation of XIAP expression in response to subtoxic, more physiological concentrations (100-500 nM) of Abeta(1-42) increases vulnerability to oxidative stress.

Amyloid beta-Peptides↗