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T Tabira

Publications and source records attributed to T Tabira.

At least 19 recordsLinked to original sources
PubMed2004

The pathogenesis of CADASIL: an update.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) appears to be the most common form of hereditary stroke disorder. CADASIL is associated with arterial smooth muscle degeneration linked to mutations in the Notch3 gene, whose product is a transmembrane receptor that functions in cell-cell communication. The pathogenesis of CADASIL remains unclear. Current research efforts are directed towards the elucidation of various features of the disorder including investigations on CADASIL-like disorders, early cognitive changes, specificity of neuroimaging for diagnosis, discovery of de novo mutations, the development of Notch3 transgenic mouse models and molecular cellular studies in Notch3 signaling. The genetics of cerebrovascular disorders (CVD) was virtually unknown until recently. Genetic associations may have been evaded because of widely variable phenotypes, even within monogenic disorders such as CADASIL. Several investigators have attempted genotype-phenotype correlation in CADASIL cases but the relationship between genetic alterations and overt manifestation of phenotype remains elusive. However, the elucidation of the genetics and pathogenesis of CADASIL have been important in further understanding of the primary vascular mechanisms that lead to ischemic blood flow and its consequences on neuronal survival. This report summarizes some of the highlights of the satellite symposium on CADASIL at Vas-Cog 2003.

Animals↗
PubMed2003

Chronic stress attenuates glucocorticoid negative feedback: involvement of the prefrontal cortex and hippocampus.

Disruption of the glucocorticoid negative feedback system is observed in approximate one half of human depressives, and a similar condition is induced in animals by chronic stress. This disruption is thought to involve down-regulation of glucocorticoid receptors (GRs) in the feedback sites of the brain. However, the responsible site of the brain has not been well elucidated. Here we examined the effects of chronic stress induced by water immersion and restraint (2 h/day) for 4 weeks followed by recovery for 10 days on the GR levels in the prefrontal cortex (PFC), hippocampus, and hypothalamus of rats using a Western immunoblot technique. In the PFC, the cytosolic GR levels were decreased, but the nuclear GR levels were not changed. In the hippocampus, the levels of cytosolic and nuclear GRs were increased. However, there were no marked changes in the GR levels in the hypothalamus. The changes in the cytosolic GR levels were confirmed at the mRNA level by an in situ hybridization technique. We next examined the suppressive effects of dexamethasone (DEX) infusions into these regions on the circulating corticosterone levels. When DEX was infused into the PFC or hippocampus of the chronically stressed rats, the suppressive response to DEX was abolished, but the response was normal in the hypothalamus. In addition, when DEX was injected systemically to the chronically stressed rats, the suppressive response to DEX was significantly attenuated. These results suggest that the abnormal changes in GRs in the higher centers of the hypothalamo-pituitary-adrenal axis are involved in the chronic stress-induced attenuation of the feedback. Since dysfunction of the PFC or hippocampus is implicated in the pathogenesis of depression, the present findings would help to understand the mechanisms underlying the disrupted feedback system and its relation to brain dysfunction in depression.

Animals↗
PubMed2002

Significance of intracellular Abeta42 accumulation in Alzheimer's disease.

Abeta plays a pivotal role in the pathogenesis of Alzheimer's disease (AD), but it is still obscure how it causes AD. We have established transgenic mice carrying wild-type or familial Alzheimer's disease (FAD) mutant-type presenilin 1 (PS1). In these mice, the number of cortical and hippocampal neurons decreased along with age in mutant mice. In addition, the old mutant mice showed a significant increase of dark neurons by silver staining and the number of neurons with intracellular Abeta42 by immunohistochemistry. Our extended study also showed a significant increase of intracellular Abeta42-positive neurons in isolated cases of AD as well as in PS1 mutant FAD cases. These neurons frequently showed apoptotic staining. However, coincidence of apoptotic markers and intraneuronal neurofibrillary tangles (NFT) was insignificant. Notably intraneuronal Abeta42-labeling was frequently seen in a case of AD showing cotton-wool type senile plaques with a few NFT positive neurons and dystrophic neurites. These results indicate that intraneuronal deposition of Abeta42 is important in the pathogenesis of AD.

Aged↗
PubMed2001

Effect of chronic stress on cholinergic transmission in rat hippocampus.

We previously demonstrated that chronic stress impaired prefrontal cortex-sensitive working memory, but not reference memory. Since the hippocampal cholinergic system is also involved in these memories, we examined the effects of chronic stress on cholinergic transmission in the rat hippocampus. A microdialysis study revealed that the stress did not affect the basal acetylcholine release, but enhanced the KCl-evoked response. These results suggest that cholinergic transmission in the chronically stressed hippocampus does not contribute to working memory impairment, but it may be involved in maintenance of reference memory.

Acetylcholine↗
PubMed2001

Three novel alternatively spliced isoforms of the human beta-site amyloid precursor protein cleaving enzyme (BACE) and their effect on amyloid beta-peptide production.

Three novel alternatively spliced transcripts of the beta-site amyloid precursor protein cleaving enzyme (BACE) were cloned from human brain. Alternative splicing of the RNA occurs at an internal donor in exon 3 and/or an internal acceptor in exon 4. The splicing events lead to a deletion of 25 (BACE-I-476), 44 (BACE-I-457) and 69 (BACE-I-432) amino acids and the latter two caused the loss of two of four N-linked glycosylation sites. Although the mature form of BACE-501 was resistant to endoglycosidase H treatment, glycosylated forms of BACE-I-457 and BACE-I-476 were sensitive. This result suggests that BACE-I-457 and BACE-I-476 underwent different post-translational modifications. Moreover, the beta-secretase activity of BACE-I-457 and BACE-I-476 was significantly weaker than that of BACE-501. Thus, these isoforms may contribute to a physiological function of BACE.

Alternative Splicing↗
PubMed2001

Costimulation-dependent modulation of experimental autoimmune encephalomyelitis by ligand stimulation of V alpha 14 NK T cells.

Experimental autoimmune encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease that can be protected against by stimulating regulatory cells. Here we examined whether EAE can be purposefully modulated by stimulating Valpha14 NK T cells with the CD1d-restricted ligand alpha-galactosylceramide (alpha-GC). EAE induced in wild-type C57BL/6 (B6) mice was not appreciably altered by injection of alpha-GC. However, EAE induced in IL-4 knockout mice and IFN-gamma knockout mice was enhanced or suppressed by alpha-GC, respectively. This indicates that the IL-4 and IFN-gamma triggered by alpha-GC may play an inhibitory or enhancing role in the regulation of EAE. We next studied whether NK T cells of wild-type mice may switch their Th0-like phenotype toward Th1 or Th2. Notably, in the presence of blocking B7.2 (CD86) mAb, alpha-GC stimulation could bias the cytokine profile of NK T cells toward Th2, whereas presentation of alpha-GC by CD40-activated APC induced a Th1 shift of NK T cells. Furthermore, transfer of the alpha-GC-pulsed APC preparations suppressed or enhanced EAE according to their ability to polarize NK T cells toward Th2 or Th1 in vitro. These results have important implications for understanding the role of NK T cells in autoimmunity and for designing a therapeutic strategy targeting NK T cells.

Amino Acid Sequence↗
PubMed2001

Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia.

BACKGROUND: Mutations in the tau gene have been reported in families with frontotemporal dementia (FTD) linked to chromosome 17. It remains uncertain how commonly such mutations are found in patients with FTD or non-Alzheimer dementia with or without a positive family history. OBJECTIVE: To determine the frequency of tau mutations in patients with non-Alzheimer dementia. PATIENTS AND METHODS: One hundred one patients with non-Alzheimer, nonvascular dementia, most thought to have FTD. Of these, 57 had a positive family history of dementia. Neuropathologic findings were available in 32. The tau gene was sequenced for all exons including flanking intronic DNA, portions of the 3' and 5' untranslated regions, and at least 146 base pairs in the intron following exon 10. RESULTS: Overall, the frequency of the tau mutations was low, being 5.9% (6/101) in the entire group. No mutations were found in the 44 sporadic cases. However, 6 (10.5%) of the 57 familial cases and 4 (33%) of the 12 familial cases with tau pathologic findings had mutations in the tau gene. The most common mutation was P301L. CONCLUSIONS: We conclude that tau mutations are uncommon in a neurology referral population with non-Alzheimer dementia, even in those with a clinical diagnosis of FTD. However, a positive family history and/or tau pathologic findings increase the likelihood of a tau mutation. There must be other genetic and nongenetic causes of FTD and non-Alzheimer dementia, similar to the etiologic heterogeneity present in Alzheimer disease.

Chromosomes, Human, Pair 17↗
PubMed2001

Familial frontotemporal dementia and parkinsonism with a novel mutation at an intron 10+11-splice site in the tau gene.

We report a case of familial frontotemporal dementia and parkinsonism characterized by early onset with mental retardation. The patient died at the age of 54; neuronal loss was severe in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus and dentate nucleus. Anti-tau-positive fibrillary changes were observed in neurons and glia in these regions. Although the patient had 2 novel point mutations of the tau gene, P301P (CCG to CCA) and an intron 10+11-splice site (T to C), exon trapping analysis indicated that the latter was pathogenic.

Brain↗
PubMed2001

Chronic stress differentially regulates glucocorticoid negative feedback response in rats.

Exposure to chronic stress is thought to play an important role in the etiology of depression. In this disorder, a disrupted negative feedback response to exogenous glucocorticoids on cortisol secretion has been indicated. However, the regulation of glucocorticoid negative feedback by chronic stress is not fully understood. In the present study, we investigated the effects of chronic stress administered by water immersion and restraint (2 h/day) for four weeks on the glucocorticoid feedback in rats. In the acutely (one-time) stressed rats, the basal plasma corticosterone (CORT) level was markedly elevated, remained at high levels for 5 h after the termination of stress, and then decreased. In the chronically stressed rats, the CORT level was initially elevated similarly, but rapidly decreased at 2 h. In the dexamethasone (DEX) suppression test, the peak CORT level in response to stress was not suppressed by DEX in the acutely stressed rats, but was significantly suppressed in the chronically stressed rats. In contrast, the suppressive effects of DEX on the basal CORT secretion in naive rats were attenuated in the chronically stressed rats. In the chronically stressed hippocampus, which plays an important role in the regulation of the glucocorticoid feedback response, the binding of [3H]DEX was decreased and the increased response of activator protein-1 induced by acute stress was abolished. These results suggest that chronic stress induces a hypersuppressive state for induced CORT secretion in response to acute stress, which is caused by partial habituation, coping, and adaptation to the stressor, whereas it induces a hyposuppressive state for the basal CORT secretion, which is caused by glucocorticoid receptor downregulation. These mechanisms may be involved in the stress-induced neural abnormalities observed in depression.

Adrenal Glands↗
PubMed2001

Pro-apoptotic effect of presenilin 2 (PS2) overexpression is associated with down-regulation of Bcl-2 in cultured neurons.

Presenilin 2 (PS2) is a polytopic membrane protein that is mutated in some cases of familial Alzheimer's disease (AD). The normal functions of PS2 and its pathogenic role in AD remain unclear. We investigated the biological role of this protein in neurons, using adenovirus-mediated transduction of the PS2 gene into rat primary cortical neurons. Immunocytochemical analyses demonstrated increased PS2 immunoreactivity in most neurons infected with recombinant adenoviruses expressing PS2. Neurons infected with wild-type or mutant (N141I) PS2-expressing adenoviruses showed a significant increase in basal cell death, compared with those infected with control beta-galactosidase-expressing adenovirus. Moreover, PS2 overexpression markedly increased neuronal susceptibility to staurosporine-induced apoptosis. Mutant PS2 was more effective in enhancing apoptosis than its wild-type counterpart. Staurosporine-induced death was significantly inhibited by a specific caspase 3 inhibitor. Western analyses revealed that Bcl-2 protein expression was specifically down-regulated in neurons overexpressing PS2, which temporally corresponded to the accumulation of C- and N-terminal fragments of PS2. Additionally, expression of mutant, but not wild-type PS2, increased the production of beta-amyloid protein (Abeta) 42. These data collectively suggest that the pro-apoptotic effect of PS2 is mediated by down-regulation of Bcl-2. PS2 mutations may increase the susceptibility of neurons to apoptotic stimuli by perturbing the regulation of cell death.

Adenoviridae↗
PubMed2001

Motoneuron pool excitability of hemiplegic patients: assessing recovery stages by using H-reflex and M response.

OBJECTIVES: To compare the excitability of the motoneuron pools of both the spastic and the unimpaired sides of patients with hemiplegia with a new method by using H-reflexes and M responses. The method determines the ratio of the developmental slope of the H-reflex (Hslp) to the slope of the M response (Mslp). We also examined the relation between the Brunnstrom stages and the Hslp/Mslp. DESIGN: Experiment. SETTING: Electrophysiologic experimental laboratory in a Japanese medical school. PATIENTS: Fifteen hemiplegic patients (9 men, 6 women; age range, 48-71yr; mean, 60yr) with spasticity caused by a stroke. INTERVENTIONS: The subject was instructed to relax while seated in a reclining chair with his foot fixed on an immobile pedal. After the soleus H-reflex and M responses on one side were recorded, the same experimental procedures were carried out on the other side. MAIN OUTCOME MEASURES: Hslp/Mslp Brunnstrom stages. RESULTS: Hslp/Mslp had better predictive value than conventional indicators of motoneuron pool excitability. Hslp/Mslp appeared to be a better match for the bell-shaped pattern of the Brunnstrom stages. CONCLUSION: Hslp/Mslp is the preferred index for evaluating the motoneuron pool excitability of the spastic side of hemiplegic patients.

Aged↗
PubMed2001

CXCR4 is the primary receptor for feline immunodeficiency virus in astrocytes.

Feline astrocytes were productively infected with the Crandell feline kidney (CrFK) cell-adapted feline immunodeficiency virus (FIV) Petaluma strain in a primary culture. They expressed mRNA of CXCR4, and the FIV infection was blocked by stromal cell-derived factor 1alpha (SDF-1alpha), SDF-1beta, or the bicyclam AMD3100 in a dose-dependent manner. These observations suggest that, like FIV infection in CrFK cells and lymphocytes, the virus uses CXCR4 as a primary receptor for infecting astrocytes and this can be a possible natural model for AIDS dementia complex.

AIDS Dementia Complex↗
PubMed2001

Decreased expression of MAP-2 and GAD in the brain of cats infected with feline immunodeficiency virus.

HIV-1 infection is often complicated by the dysfunction of central nervous system (CNS). Degenerative neuronal changes as well as neuronal loss have been documented in individuals with acquired immunodeficiency syndrome. Feline immunodeficiency virus (FIV) causes similar CNS manifestation and FIV infected cats provide an animal model for human immunodeficiency virus infection in humans. In this study, we examined the brain of FIV-infected cats and controls with immunohistochemical techniques using antibodies to microtubule-associated protein 2 (MAP-2) and glutamic acid decarboxylase (GAD). We found a significant decrease in expression of MAP-2 and GAD in neurons of infected animals compared to controls. In contrast, the expression of neurofilaments and glial fibrillary acidic protein was rather increased. The changes observed in the brain were similar to those seen in humans undergoing the normal aging process as well as those suffering from neurological diseases like Alzheimer's disease and other dementing disorders. These changes in the feline brain give insight into the deleterious effects of FIV on the CNS.

Animals↗
PubMed2001

Changes in brain morphology in Alzheimer disease and normal aging: is Alzheimer disease an exaggerated aging process?

BACKGROUND AND PURPOSE: Whether Alzheimer disease (AD) represents exaggerated aging rather than a disease is controversial. Data about the effects of normal aging on the human brain are essential for clarifying this issue; however, whether coherent common patterns of regional morphologic brain changes emerge in the normal aged brain is unclear. Clarification of regional morphologic changes in the brain associated with normal aging and AD was sought using MR imaging. METHODS: Ninety-two healthy volunteers and 26 mildly to moderately impaired patients with AD participated. Images were anatomically normalized, and voxel-by-voxel analyses were done. RESULTS: In healthy volunteers, an age-related decline in the volume of the prefrontal cortex, insula, anterior cingulate gyrus, superior temporal gyrus, inferior parietal lobule, and precuneus was found. These decreases might contribute to the cognitive changes during normal aging. In patients with AD, a significant reduction of gray matter volume in the hippocampal formation and entorhinal cortex bilaterally was noted. CONCLUSION: Morphologic changes associated with normal aging are clearly different from those seen with AD.

Adolescent↗
PubMed2000

Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein.

Using the yeast two-hybrid system, we screened for proteins interacting with presenilin 2 (PS2) and cloned DRAL. DRAL is an LIM-only protein containing four LIM domains and an N-terminal half LIM domain. Previously DRAL has been cloned as a co-activator of the androgen receptor and as a protein interacting with a DNA replication regulatory protein, hCDC47. Our yeast two-hybrid assay showed that DRAL interacted with a hydrophilic loop region (amino acids 269-298) in the endoproteolytic N-terminal fragment of PS2, but not that of PS1, although the region 269-298 of PS2 and the corresponding PS1 sequence differ by only three amino acids. Each point mutation within this region, R275A, T280A, Q282A, R284A, N285A, P287T, I288L, F289A and S296A, in PS2 abolished the binding. This suggests that DRAL recognizes the PS2 structure specifically. The in vitro interaction was confirmed by affinity column assay and the physiological interactions between endogenous PS2 and DRAL by co-immunoprecipitation from human lung fibroblast MRC5 cells. Furthermore, in PS2-overexpressing HEK293 cells, we found an increase in the amount of DRAL in the membrane fraction and an increase in the amount of DRAL that was co-immunoprecipitated with PS2. The potential role of DRAL in the cellular signaling suggests that DRAL functions as an adaptor protein that links PS2 to an intracellular signaling.

Alzheimer Disease↗