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Takeshi Tabira

Publications and source records attributed to Takeshi Tabira.

At least 19 recordsLinked to original sources
PubMed2004

Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease.

The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 with p53 mRNA elevation in guinea-pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.

Aged↗
PubMed2004

Amino-truncated amyloid beta-peptide (Abeta5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer's disease brain.

Caspase activation and apoptosis are implicated in Alzheimer's disease (AD). In view of the finding that the amyloid precursor protein (APP) undergoes caspase-mediated cleavage in the cytoplasmic region, we analyzed amyloid beta-peptide (Abeta) production in human neuronal and nonneuronal cells expressing wild-type APP and the caspase-cleaved form of APP (APPDeltaC). Biochemical analyses, including immunoprecipitation/mass spectrometry, revealed that APPDeltaC-expressing cells secrete increased levels of amino-terminally truncated Abeta5-40/42 and reduced levels of Abeta1-40/42, compared with wild-type APP-expressing cells. We propose that Abeta5-40/42 is derived from alternative beta-cleavage of APP by alpha-secretase-like protease(s), based on data from treatment of cells with inhibitors of BACE and alpha-secretase. Apoptosis induction resulted in this alternative cleavage of APP in wild-type APP-expressing cells. Moreover, immunohistochemical staining of the AD brain with an end-specific antibody to Abeta5-40/42 revealed peptide deposits in vascular lesions with amyloid angiopathy. The data collectively suggest that caspase cleavage of APP leads to increased production and deposition of Abeta5-40/42 in the AD brain, and highlight the significance of amino-truncated Abeta in the pathogenesis of AD.

Alzheimer Disease↗
PubMed2004

Endogenous glucocorticoids are essential for maintaining prefrontal cortical cognitive function.

Glucocorticoid hormones are important in the maintenance of many brain functions. Although their receptors are distributed abundantly throughout the brain, including the prefrontal cortex (PFC), it is not clear how glucocorticoid functions, particularly with regard to cognitive processing in the PFC. There is evidence of PFC cognitive deficits such as working memory impairment in several stress-related neuropsychiatric disorders, including depression, schizophrenia, and Parkinson's disease. Disruption of the hypothalamo-pituitary-adrenal (HPA) system, which is characterized by attenuated glucocorticoid negative feedback, is also observed. In rats, chronic stress induces working memory impairment as a result of decreased dopaminergic transmission in the PFC. These chronically stressed rats also show HPA disruption; this is caused in part by a reduced glucocorticoid response in the PFC. These findings implicate reduced glucocorticoid actions in working memory impairment. In the present study, we examined the effects of the suppression of endogenous glucocorticoids by adrenalectomy (ADX) on working memory in rats and explored the involvement of PFC dopaminergic activities in memory. The ADX impaired working memory, decreased dopamine release, and upregulated D1 receptors in the PFC. These dysfunctions were prevented by corticosterone replacement that reproduced normal physiological plasma levels, indicating that suppression of glucocorticoids causes these dysfunctions. Moreover, the ADX-induced working memory impairment was ameliorated by intra-PFC infusions of a D1 receptor agonist, SKF 81297. Thus, suppression of glucocorticoids impaired working memory through a D1 receptor-mediated hypodopaminergic mechanism in the PFC. This finding indicates that endogenous glucocorticoids are essential for maintaining PFC cognitive function and suggests that HPA disruption contributes to PFC cognitive deficits.

Adrenalectomy↗
PubMed2004

Glypican-1 as an Abeta binding HSPG in the human brain: its localization in DIG domains and possible roles in the pathogenesis of Alzheimer's disease.

Previous studies have suggested that heparan sulfate proteoglycans (HSPGs) play a role in deposition of beta-amyloid protein (Abeta) in the Alzheimer's disease (AD) brain. In the present study, we demonstrated that glypican-1 can bind fibrillar Abeta, and the binding is mainly mediated by heparan sulfate (HS) chains. Further analysis revealed that glypican-1 is the major HSPG localized in detergent-insoluble glycosphingolipid-enriched (DIG) domains where all machineries for Abeta production exist and Abeta is accumulated as monomeric and oligomeric forms. Immunohistochemical studies demonstrated that glypican-1 is localized in primitive plaques as well as classic plaques. Moreover, overexpression of glypican-1 and amyloid precursor protein in SH-SY5Y cells resulted in reduced cell viability and made cells more susceptible to thapsigargin-induced stress and Abeta toxicity. The results raise the possibility that glypican-1 interacts with oligomerized or polymerized Abeta in such a specific compartment as DIG, resulting not only in amyloid deposition in senile plaques of AD brain, but also in accelerating neuronal cell death in response to stress and Abeta.

Aged↗
PubMed2004

Association between tau polymorphism and male early-onset Alzheimer's disease.

Neurofibrillary tangles, containing hyperphosphorylated microtubule-associated protein tau, are one of the major pathological hallmarks of Alzheimer's disease. To investigate a possible association between tau genotypes and the risk of Alzheimer's disease, we screened for polymorphisms in the tau gene and found a novel polymorphism IVS11 + 90G --> A. A case-control study (874 patients and 678 controls) showed a significant association between possession of the A allele and male Alzheimer's disease with early-onset (age of onset before 65, odds ratio = 2.65; 95% confidence interval 1.30-5.42), suggesting that age and gender modify the risk effect. However, we failed to replicate the reported association between the Saitohin gene located in the tau intron 9 and Japanese Alzheimer's disease.

Adult↗
PubMed2004

Enhanced generation of intracellular Abeta42 amyloid peptide by mutation of presenilins PS1 and PS2.

The accumulation of amyloid beta-peptide (Abeta) in the brain is a critical pathological process in Alzheimer's disease (AD). Recent studies have implicated intracellular Abeta in neurodegeneration in AD. To investigate the generation of intracellular Abeta, we established human neuroblastoma SH-SY5Y cells stably expressing wild-type amyloid precursor protein (APP), Swedish mutant APP, APP plus presenilin 1 (PS1) and presenilin 2 (PS2; wild-type or familial AD-associated mutant), and quantified intracellular Abeta40 and Abeta42 in formic acid extracts by sensitive Western blotting. Levels of both intracellular Abeta40 and Abeta42 were 2-3-fold higher in cells expressing Swedish APP, compared with those expressing wild-type APP. Intracellular Abeta42/Abeta40 ratios were approximately 0.5 in these cells. These ratios were increased markedly in cells expressing mutant PS1 or PS2 compared with those expressing their wild-type counterparts, consistent with the observed changes in secreted Abeta42/Abeta40 ratios. High total levels of intracellular Abeta were observed in cells expressing mutant PS2 because of a marked elevation of Abeta42. Immunofluorescence staining additionally revealed more intense Abeta42 immunoreactivity in mutant PS2-expressing cells than in wild-type cells, which was partially colocalized with immunoreactivity for the trans-Golgi network and endosomes. The data collectively indicate that PS mutations promote the accumulation of intracellular Abeta42, which appears to be localized in multiple subcellular compartments.

Amyloid beta-Peptides↗
PubMed2004

Development of a safe oral Abeta vaccine using recombinant adeno-associated virus vector for Alzheimer's disease.

A new oral vaccine for Alzheimer's disease was developed using recombinant adeno-associated virus vector carrying Abeta cDNA (AAV/Abeta). Oral administration of the vaccine without adjuvant induced the expression and secretion of Abeta1-43 or Abeta1-21 in the epithelial cell layer of the intestine in amyloid precursor protein transgenic mice. Serum antibody levels were elevated for more than six months, while T cell proliferative responses to Abeta was not detected. Brain Abeta burden was significantly decreased compared to the control without inflammatory changes. This oral AAV/Abeta vaccine seems to be promising for prevention and treatment of Alzheimer's disease.

Administration, Oral↗
PubMed2003

A unifying model for functional difference and redundancy of presenilin-1 and -2 in cell apoptosis and differentiation.

Mutations in genes encoding the highly homologous proteins presenilin-1 and -2 (PS1 and PS2) are linked to the early onset of Alzheimer's disease (AD). Here, we report that polyclonal antibodies against Xenopus PSbeta (PS2), but not PSalpha (PS1), suppress the in vitro apoptotic activation of Xenopus egg extracts. To clarify the relationship between structural and functional differences in presenilins, we searched for presenilin homologues in various living sources, and found that presenilins were divided into three distinct groups, named alpha-, beta- and gamma-types, based on the size of the large hydrophilic loop (HL) regions as follows: HLalpha/HLbeta/HLgamma=4:3:6. No such size conservations were found in the N-terminal (NT) hydrophilic regions. Phylogenetic studies revealed that the presenilin genes were duplicated independently in different lineages of phyla/divisions, suggesting that there were functional requirements for and constraints on the generation and conservation of these HL sizes. On the basis of these findings, we propose a model postulating that both PS1 and PS2 can be differentiative or apoptotic when they are proteolytically processed within the HL regions or not, respectively, and PS1 may be more sensitive than PS2 to auto-proteolytic cleavage due to the larger size of the HL region of the former. Furthermore, the model assumes that C-terminal fragments (CTF) stabilized by phosphorylation may inhibit both the activities due to the dominant-negative effect. The model explains not only the functional redundancy but also apparently conflicting observations reported so far for PS1 and PS2.

Animals↗
PubMed2003

Differential expression of presenilin-alpha and -beta (PSalpha and PSbeta) in Xenopus laevis: embryonic phosphorylation of PSalpha.

Mutations in genes encoding the highly homologous proteins, presenilin-1 and -2 (PS1 and PS2), are linked to the development of early-onset Alzheimer's disease. On the other hand, presenilins are known to play a critical role(s) in cell fate decisions during embryonic development in Caenorhabditis elegans. The messenger RNAs (mRNAs) of amphibian presenilin homologues PSalpha and PSbeta are most abundantly synthesized in the brain and the ovary, but are differentially degraded upon oocyte maturation and at the midblastula transition (MBT), respectively. In this study, we examined the spatiotemporal distribution of PSalpha and PSbeta proteins and their post-translational modification. The results were essentially consistent with the mRNA data and revealed moreover that PSalpha was present exclusively as processed molecules in the early embryos, while PSbeta was present mainly as unprocessed molecules (90%). Furthermore, the C-terminal fragment (CTF) of PSalpha was phosphorylated upon oocyte maturation and dephosphorylated at MBT, while no phosphorylation of the PSbeta CTF was detectable. Human PS1 CTF exogenously injected was also phosphorylated in Xenopus oocytes induced to mature in vitro by progesterone treatment. Two phosphorylation loci were mapped at Thr(320) and Ser(334) in the hydrophilic loop region of PSalpha. Our results suggest that PS1 and PS2 may play different roles under physiological conditions despite their high structural similarity.

Amino Acid Sequence↗
PubMed2003

Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis.

We have examined Notch3 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose samples were submitted to us in Japan. The subjects were composed of 21 Japanese, 1 Iranian, 1 Korean and 1 Canadian families. Mutations in the Notch3 gene were found in 7 of 24 families examined. These were R133C in two unrelated Japanese families, and R213K, C174F and R169C in each Japanese family. In addition, we have found R90C in an Iranian family and C174R in a Korean family. Thus, contribution of Notch3 gene mutations is less than one fourth of Japanese CADASIL families, suggesting the existence of other causative genes in CADASIL. It is also of interest to know that Notch3 mutant CADASIL exists in other Asian countries. We next examined the localization of Notch3 protein in the tissue by immunohistochemistry. It was restricted to the wall of arterioles in the brain and other organs. In the brain, there was no difference in the staining pattern among arterioles in the cortex, white matter and meninges. The staining was negative in the venule and capillaries as well as in neurons and glial cells. From the staining pattern, it was recognized to be expressed in the vascular smooth muscle cells in the adult tissue. In an autopsy case with R213K mutation, we could see numerous cerebral infarcts and arteriole wall degeneration with deposits of granular osmiophilic material (GOM). However, it is interesting to note that occlusion of arterioles was rarely observed and the GOM was negative for Notch3 staining. These findings suggest that hemodynamic abnormalities due to smooth muscle cell degeneration may be important in the pathogenesis of CADASIL.

Age of Onset↗
PubMed2003

A clinical and pathological study of a Japanese case of Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex with family history.

This report concerns a Japanese family with neuropathological findings consistent with amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) in the Island of Guam. The proband was a 68-year-old woman with an 8-year history of parkinsonism which was followed by psychiatric symptoms and neurogenic amyotrophy 5 years after the onset. She had a family history of parkinsonism associated with dementia in all of her three siblings. They grew up in the Hobara village, a focus of amyotrophic lateral sclerosis in the Kii Peninsula of Japan in their childhood. Their parents were not consanguineous nor natives of the Kii Peninsula. The brain weight was 1040 g and there were mild frontal lobe atrophy, moderate atrophy of pes hippocampi, decoloration of the substantia nigra and locus coeruleus, and atrophy of the anterior root of the spinal cord. The microscopic examinations revealed degeneration of CA1 portion of the hippocampus to the parahippocampus gyrus, substantia nigra, locus coeruleus and spinal anterior horn with Bunina bodies. The spinal pyramidal tracts also mildly degenerated. Neurofibrillary tangles (NFT) were observed in the cerebral cortex, especially in the cortices from hippocampus to lateral occipitotemporal gyri, basal nucleus of Mynert, basal ganglia, thalamus, substantia nigra and widespread regions of the central nervous system through the brainstem to spinal cord including the nucleus of Onufrowitcz. In spite of a small amount of the senile plaques in the cerebral cortex and Lewy bodies in the substantia nigra and locus coeruleus, abundant NFT were distributed mainly in the third layer of the cerebral cortex, which is the characteristic feature of ALS/PDC. Thus, this was likely to be an ALS/PDC case outside the Guam Island. A tau mutation was not found on DNA analysis.

Aged↗
PubMed2003

Saiko-ka-ryukotsu-borei-to, a herbal medicine, ameliorates chronic stress-induced depressive state in rotarod performance.

Exposure to chronic stress is thought to play an important role in the etiology of depression. This disorder has been shown to involve disruption of the hypothalamo-pituitary-adrenal (HPA) system and dysfunction of the prefrontal cortex (PFC). We have demonstrated that chronic stress in rats induces similar HPA disruption or a depressive state caused by a reduction of dopaminergic and serotonergic transmission in the PFC. We have also shown that saiko-ka-ryukotsu-borei-to, a herbal medicine, prevents such chronic stress-induced HPA disruption. However, the behavioral and neurochemical bases of this drug remain unclear. Here we examined the effects of saiko-ka-ryukotsu-borei-to on the depressive behavioral state and the reduction of transmission resulting from chronic stress. The chronic stress was induced by water immersion and restraint (2 h/day) for 4 weeks followed by recovery for 10 days. The treatment with saiko-ka-ryukotsu-borei-to (100, 300, or 1000 mg/kg p.o.) ameliorated the stress-induced depressive state in a dose-dependent manner, evaluated by a rotarod test. A microdialysis study indicated that the drug treatment significantly prevented the chronic stress-induced decreases in extracellular concentrations of dopamine and serotonin in the PFC. These results suggest that saiko-ka-ryukotsu-borei-to ameliorates the chronic stress-induced depressive state based on the prevention of PFC dysfunction. These findings provide important information for treatment of depression.

Animals↗
PubMed2003

Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex--tauopathy without mutations in the tau gene?

We present the clinical and genetic characteristics of a Japanese patient with neuropathologically confirmed familial amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). The 68-year-old proband with an 8-year history of parkinsonism and neurogenic amyotrophy and her three siblings suffering from parkinsonism associated with dementia originated from the Kii Peninsula of Japan. The proband's brain exhibited mild frontal lobe atrophy, moderate atrophy of the pes hippocampi, decoloration of the substantia nigra and locus coerules, and atrophy of the anterior root of the spinal cord. Microscopic examinations revealed degeneration of the CA1 portion of the hippocampus to the parahippocampus gyrus, substantia nigra, locus coerules and the spinal anterior horn with Bunina bodies. Neurofibrillary tangles (NFTs) were observed in widespread regions of the central nervous system through the cerebral cortex to the spinal cord. The predominant distribution of NFTs in the the third layer of the cerebral cortex was compatible with the characteristic feature of ALS/PDC in Guam. No tau mutation was found in the proband. The lack of mutations in the tau gene not only in this patient but also in earlier reported cases of ALS in the Western Pacific seems to suggest that other genetic factors may be contributing to ALS/PDC.

Aged↗