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Biomedical subjects

T Tabira

Publications and source records attributed to T Tabira.

At least 55 records · Page 3Linked to original sources
PubMed1999

No effect of anti-leprosy drugs in the prevention of Alzheimer's disease and beta-amyloid neurotoxicity.

There is continuing controversy as to whether or not anti-leprosy drugs prevent Alzheimer's disease (AD). Therefore, we examined the effect of anti-leprosy drugs on the prevalence of AD in leprosy patients, and also investigated the effect of anti-leprosy drugs on amyloid beta-protein (Abeta)-induced neurotoxicity in vitro. The present study suggests that anti-leprosy treatments do not prevent the onset of AD. None of our data found anti-leprosy drugs (dapsone, rifampicin, clofazimine, minomycin or ofloxacin) had any effect on Abeta neurotoxicity. It is now important to examine the infection of Mycobacterium leprae in the central nervous system to clarify the reason for the low prevalence of senile dementia, and low frequency of Abeta deposition in leprosy patients.

Aged↗
PubMed1999

Effects of presenilin N-terminal fragments on production of amyloid beta peptide and accumulation of endogenous presenilins.

To clarify the effects of the proteolytic cleavage of presenilin 1 (PS1) and presenilin 2 (PS2) proteins on their functions, we established stable cell lines which expressed the physiologically cleaved N-terminal fragment (NTF) with or without mutations of familial Alzheimer's disease (FAD). We found that exogenous expression of the PS1-NTF or PS2-NTF harboring FAD mutations was insufficient for increased production of amyloidogenic A beta X-42 peptide and that the overexpressed NTFs had no effect on the accumulation of endogenous presenilin fragments.

Alzheimer Disease↗
PubMed1999

A distinct familial presenile dementia with a novel missense mutation in the tau gene.

We report a Japanese family with early onset hereditary frontotemporal dementia and a novel missense mutation (Ser305Asn) in the tau gene. The patients presented with personality changes followed by impaired cognition and memory as well as disorientation, but minimal Parkinsonism. Imaging studies showed fronto-temporal atrophy with ventricular dilatation more on the left, and postmortem examination of the brain revealed numerous neurofibrillary tangles (NFTs) with an unusual morphology and distribution. Silver-stained sections showed ring-shaped NFTs partially surrounding the nucleus that were most prominent in frontal, temporal, insular and postcentral cortices, as well as in dentate gyrus. Cortical NFTs were restricted primarily to layer II, and were composed of straight tubules. Numerous glial cells containing coiled bodies and abundant neuropil threads were detected in cerebral white matter, hippocampus, basal ganglia, diencephalon and brain stem, but no senile plaques or other diagnostic lesions were seen. Both the glial and neuronal tangles were stained by antibodies to phosphorylation-independent and phosphorylation-dependent epitopes in tau. Thus, this novel mutation causes a distinct familial tauopathy.

Adult↗
PubMed1999

Isolation of human delta-catenin and its binding specificity with presenilin 1.

We screened proteins for interaction with presenilin (PS) 1, and cloned the full-length cDNA of human delta-catenin, which encoded 1225 amino acids. Yeast two-hybrid assay, GST binding assay and immunoprecipitation demonstrated that delta-catenin interacted with a hydrophilic loop region in the endoproteolytic C-terminal fragment of PS1, but not with that of PS-2. These results suggest that PS1 and PS2 partly differ in function. PS1 loop fragment containing the pathogenic mutation retained the binding ability. We also found another armadillo-protein, p0071, interacted with PS1.

Amino Acid Sequence↗
PubMed1999

X11L2, a new member of the X11 protein family, interacts with Alzheimer's beta-amyloid precursor protein.

We screened proteins for interaction with Alzheimer's beta-amyloid precursor protein (APP) and cloned a new member of the X11 protein family, X11L2. The PID/PTB element of X11L2 protein interacted with the intracellular domain of APP by GST binding assay, and in vivo interaction was confirmed by coimmunoprecipitation from cell extracts overexpressing APP and HA-tagged X11L2. This gene encoded 575 amino acids and the deduced amino acid sequence was highly homologous to rat Mint3. Three protein-protein interaction domains, a PID/PTB and two PDZ elements, were conserved among the X11 protein family, and the N-terminal region of X11L2 protein had several putative SH3 binding motifs, PXXP. Unlike other members of the X11 protein family, X11L2 mRNA was expressed in various tissues.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's beta-amyloid precursor protein.

We report the cDNA sequence of human Fe65L2. The human Fe65L2 encoded 486 amino acids; the deduced amino acid sequence was shorter by 18 amino acids than the rat protein and had 86% identity to the rat protein Three protein-protein interaction domains, a WW and two PID/PTB elements, were conserved among the Fe65 protein family. Human Fe65L2 mRNA was expressed in various tissues; a transcript of about 2.2 kb was mainly expressed in the brain. A splicing variant lacking two amino acids in the first PID/PTB element was detected. We also confirmed that the carboxyl-terminal region of PID/PTB of the Fe65L2 interacted with the intracellular domain of the Alzheimer's beta-amyloid precursor protein (APP) and APP-like proteins.

Alzheimer Disease↗
PubMed1999

Identification of autoimmune T cells among in vivo expanded CD25+ T cells in multiple sclerosis.

Although clonal expansion of autoimmune T cells has been reported in multiple sclerosis (MS), very limited information is available on specificities, clonal size, or activation state of the expanded clones. Here we address the issue of clonal expansion by using a novel technique demonstrating clonotypes defined by single-strand conformation polymorphism of TCR beta-chain cDNAs. Examination of activated T cells (CD3+CD25+) isolated from the peripheral blood of MS revealed limited numbers (20 approximately 82) of expanded clones defined by single-strand conformation polymorphism clonotype. To estimate the Ag specificities of dominant clonotypes in the activated T cells, these samples were examined in parallel with Th1 T cell clones specific for myelin basic protein or proteolipid protein (PLP) derived from the same patients. Analysis of two patients demonstrated that the dominant clonotypes would contain those specific for myelin basic protein or PLP. Although the majority of the clonotypes could be detected only transiently, a PLP95-116-specific clonotype was found to persist for over 1 yr. Thus, single-strand conformation polymorphism clonotype analysis allows us to monitor the kinetics of given T cell clones in vivo and could provide useful information for designing clonotype (Id)-specific manipulation of human diseases such as MS.

Adult↗
PubMed1999

FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10.

Missense mutations and intronic mutations in the tau gene cause frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known missense mutations reduce the ability of tau to promote microtubule assembly. Intronic mutations lead to increased mRNA splicing of the alternatively spliced exon 10, resulting in an overproduction of tau isoforms with four microtubule-binding repeats. We show here that the recently identified FTDP-17 missense mutations N279K and S305N do not reduce the ability of tau to promote microtubule assembly. Instead they lead to increased splicing of exon 10, like the intronic mutations. The N279K and S305N mutations define a class of missense mutations in tau whose primary effects are at the RNA level.

Alternative Splicing↗
PubMed1999

Serial analysis of gene expression in a microglial cell line.

We used the serial analysis of gene expression (SAGE) method to systematically analyze transcripts present in a microglial cell line. Over 10,000 SAGE tags were sequenced, and shown to represent 6,013 unique transcripts. Among the diverse transcripts that had not been previously detected in microglia were those for cytokines such as endothelial monocyte-activating polypeptide I (EMAP I), and for cell surface antigens, including adhesion molecules such as CD9, CD53, CD107a, CD147, CD162 and mast cell high affinity IgE receptor. In addition, we detected transcripts that were characteristic of hematopoietic cells or mesodermal structures, such as E3 protein, A1, EN-7, B94, and ufo. Furthermore, the profile contained a transcript, Hn1, that is important in hematopoietic cells and neurological development (Tang et al. Mamm Genome 8:695-696, 1997), suggesting the probable neural differentiation of microglia from the hematopoietic system in development. Messenger RNA expression of these genes was confirmed by RT-PCR in primary cultures of microglia. Significantly, this is the first systematic profiling of the genes expressed in a microglial cell line. The identification and further characterization of the genes described here should provide potential new targets for the study of microglial biology.

Animals↗
PubMed1999

Autonomic regulation of experimental autoimmune encephalomyelitis in IL-4 knockout mice.

The effect of chemical sympathectomy induced with 6-hydroxydopamine (OHDA) on experimental autoimmune encephalomyelitis (EAE) was studied in wild type and IL-4-/- C57BL/6 (B6) mice. When actively sensitized with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, control B6 mice developed a mild form of EAE with full recovery. The sympathectomized mice developed paralysis with higher maximum disease score and did not recover completely, indicating that the sympathetic nervous system (SNS) down-modulates the process of EAE. Unexpectedly, however, sympathectomy resulted in suppression of EAE in IL-4-/- mice, implying that control of actively induced EAE by the SNS depends on the genetic background of mice. We also induced EAE by passive transfer of MOG35-55-reactive lymph node cells, and this disease was augmented by sympathectomy in both wild type and knockout animals. Further experiments showed that changes in T cell populations and the activity of antigen presenting cells might be responsible for the altered immune response and clinical course after sympathetic ablation. Our studies indicate that the absence of a single cytokine can severely alter nervous-immune system interactions.

Animals↗
PubMed1999

Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.

Familial Alzheimer disease mutations of presenilin 1 (PS-1) enhance the generation of A beta1-42, indicating that PS-1 is involved in amyloidogenesis. However, PS-1 transgenic mice have failed to show amyloid plaques in their brains. Because PS-1 mutations facilitate apoptotic neuronal death in vitro, we did careful quantitative studies in PS-1 transgenic mice and found that neurodegeneration was significantly accelerated in mice older than 13 months (aged mice) with familial Alzheimer disease mutant PS-1, without amyloid plaque formation. However, there were significantly more neurons containing intracellularly deposited A beta42 in aged mutant transgenic mice. Our data indicate that the pathogenic role of the PS-1 mutation is upstream of the amyloid cascade.

Age Factors↗
PubMed1998

Familial Alzheimer's disease genes in Japanese.

More than 40 missense mutations and a splice-site mutation in the presenilin 1 (PS-1) gene, two missense mutations of presenilin 2 (PS-2), and more than three missense mutations of amyloid precursor protein (APP) cosegregate with early onset familial Alzheimer's disease (FAD). In order to determine the incidence of mutations of these genes in Japanese patients, we screened 25 early onset FAD families, one late-onset FAD case, 33 early onset AD cases and five late-onset AD cases for mutations in the coding regions of the genes using SSCP analysis. Four different missense mutations of the PS-1 gene, including a novel mutation, Glu273Ala, were identified in five early onset FAD families and one missense mutation of PS-1 in one isolated AD patient. While no missense mutations of PS-2 were detected, four silent nucleotide substitutions were observed. Our data indicate that PS-1 mutations account for 20.0% of early onset FAD cases in Japan. Since mutations in PS-2 and APP genes were not found in the remaining cases, which could be explained only partially by apolipoprotein E epsilon4, important FAD genes or risk-factor genes remain to be identified.

Adult↗
PubMed1998

Both N-terminal and C-terminal fragments of presenilin 1 colocalize with neurofibrillary tangles in neurons and dystrophic neurites of senile plaques in Alzheimer's disease.

Presenilin 1 (PS1) is a causative gene for chromosome 14-linked familial Alzheimer's disease. The gene product is known to be cleaved into N-terminal fragments (PS1-N) and C-terminal fragments (PS1-C). To understand the pathophysiological role of PS1, we conducted immunohistochemical studies using antibodies specific for PS1-N and PS1-C in sporadic Alzheimer's disease (AD). Both antibodies showed punctuate staining exclusively in neurons and their processes in both control and AD brains. PS1-N immunolabeling colocalized with neurofibrillary tangles (NFTs) in 36% of NFT-bearing neurons and with dystrophic neurites in 28% of senile plaques (SPs). PS1-C immunolabeling colocalized with dystrophic neurites in 70% of NFT-bearing SPs and with intraneuronal NFTs in 32% of NFT-bearing neurons. Both antibodies did not detect PHF-tau-positive neuropil threads and Abeta amyloid fibrils. The colocalization was also found in 33-38 % of NFT-bearing neurons in progressive supranuclear palsy. These results indicate that both PS1-N and PS1-C fragments are deposited in part of NFT-bearing neurons and dystrophic neurites in SPs; both are the pathologic hallmarks of AD.

Alzheimer Disease↗
PubMed1998

Interleukin-3 and interleukin-3 receptors in the brain.

We have previously demonstrated that interleukin 3 (IL-3) has a neurotrophic effect on central cholinergic neurons and have demonstrated the presence of IL-3 receptor (IL-3R)beta subunits in septal cholinergic neurons by reverse-transcribed polymerase chain reaction (RT-PCR) and immunohistochemistry. In order to confirm that the expressed IL-3R is functional, we conducted experiments to show an alpha subunit of IL-3R. The alpha subunit was clearly demonstrated by RT-PCR in the central cholinergic neuronal hybrid cell line SN6, but not in its mother cell line N18TG2, and the expression was slightly upregulated after IL-3 treatment. Choline acetyltransferase and vesicular acetylcholine transporter mRNAs were significantly increased in SN6 after treatment with IL-3. Immunohistochemically, IL-3R alpha-positive cells were mainly present in the medial septal and basal forebrain region, and the stained cells were similar to choline acetyltransferase-positive cells in shape and distribution. The IL-3R alpha-positive cells slightly increased two days after fimbria-fornix transection and decreased seven days after. These findings suggest that functional IL-3 receptors are expressed in the central cholinergic neurons and contribute to some physiological roles such as the differentiation and maintenance of these neurons.

Animals↗
PubMed1998

Cloning of the cDNA encoding rat presenilin-2.

We report here the cDNA sequence of rat homologue of presenilin-2 (PS-2). The rat PS-2 cDNA encoded 448 amino acids, and the deduced amino acid sequence was highly homologous to those of the human (94.9%), mouse (96.4%) and Xenopus (70.8%). A minor splicing variant lacking a single glutamate was detected, while the product corresponding to the exon 9 deleted splicing variant observed in human was not detected.

Alternative Splicing↗
PubMed1998

Baló's concentric sclerosis in a 4-year-old Japanese infant.

We report the youngest known case with Baló's concentric sclerosis (Baló's disease), a variant of multiple sclerosis. This 4-year-old Japanese boy was diagnosed by clinical manifestations and by characteristic findings on magnetic resonance imaging (MRI). Dexamethasone was given intravenously, 3 mg twice daily for 10 days. The clinical manifestations were resolved within 2 weeks, and the MRI findings were markedly improved after 3 weeks. Following the initiation of steroid therapy, he showed remarkable clinical and physical improvement. It cannot be excluded that the clinical improvement resulted from the steroid therapy.

Brain↗