c954C-->T polymorphism in the Fe65L2 gene is associated with early-onset Alzheimer's disease.
Explore the source record for details and available documents.
Age of Onset↗
Biomedical subjects
Takeshi Tabira
Publications and source records attributed to Takeshi Tabira.
Dopamine-receptor stimulation in the prefrontal cortex ameliorates stress-induced rotarod impairment.
Exposure to chronic stress is thought to play an important role in the etiology of depression. In this disorder, dopaminergic dysfunction in the prefrontal cortex (PFC) is thought to be involved. Indeed, chronic stress reduces dopaminergic transmission in the rat PFC or induces a behaviorally depressive state. However, a relationship between the reduced dopaminergic activity and the behavior of the chronically stressed rats has not been proven. Here, we examined the effects of local application of a dopamine Type I (D(1)) receptor-specific agonist, SKF 81297, in the PFC on the chronic-stress-induced depressive state using a rotarod test. The chronic stress produced by water immersion and restraint for 4 weeks followed by recovery for 10 days impaired the rotarod performance without changing the traction performance or locomotor activity. Although intra-PFC infusion of 1 or 10 ng of SKF 81297 did not affect this impairment, 100 ng of SKF 81297 significantly ameliorated it. These results suggest that the chronic-stress-induced depressive state is caused by a D(1) receptor-mediated hypodopaminergic mechanism in the PFC. These findings will further understanding of the mechanisms underlying the pathophysiology of depression.
Animals↗
Microtubule associated protein (tau) gene variability in patients with frontotemporal dementia.
Frontotemporal dementia represents up to 10% of all dementias and is, next to Alzheimer's disease and Lewy body disease, the third most common cause of degenerative dementia. The term "frontotemporal dementia" covers a range of conditions, including Pick's disease, frontal lobe degeneration and dementia associated with motor neurone disease. Neuropathologically FTD is characterised by atrophy of the frontal and temporal lobes of the cerebral cortex, often with additional subcortical changes. Both familial and more frequently sporadic forms of FTD can be recognised. Recently, mutations in the microtubule-associated protein (tau) gene have been found in families with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The identification of mutations in the tau gene indicates that the protein plays a central role in the process of neurodegeneration. Epidemiology of frontotemporal dementias in Poland remains still unknown. A prevalence of tau mutations among Polish patients has not been established yet. Here, we report results of a mutational analysis of the tau gene among Polish FTD patients. No pathogenic mutation was found in the analysed sample. The study confirmed that the frequency of tau mutations is very low and depends strongly on the clinical criteria used to select patients. Mutations in the tau gene account only for a small number of FTD cases with a clear autosomal dominant pattern of disease inheritance. Therefore there should exist additionalgenetic and non-genetic factors contributing to the pathogenesis of both familial (linked and non-linked to chromosome 17) and sporadic forms of FTD.
Aged↗
A novel mutation at position +11 in the intron following exon 10 of the tau gene in FTDP-17.
Mutations in the microtubule-associated tau gene are responsible for frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). A reduced ability of the mutated microtubule-associated tau protein to interact with microtubules causes microtubule destabilization leading to deleterious effects on axonal transport and the formation of tau filaments. Here, we describe a new mutation of the tau gene, a T --> C transition at position +11 of the intron following exon 10 (T --> C 3'E10 +11) in the family showing frontotemporal dementia with very early age of onset (the first decade of proband's life). The T -->C 3'E10 +11 mutation caused a large increase in the proportion of transcripts containing exon 10 detected by exon-trapping analysis. Our study confirmed that the T --> C 3'E10 +11 mutation, as the other 5' splice site mutations of tau exon 10, modifies alternative splicing of exon 10.
Animals↗
[Significance of intracellular A beta in Alzheimer's disease].
It is now widely accepted that beta-amyloid has a central role in the pathogenesis of Alzheimer's disease (AD). It is mainly composed of aggregated A beta protein and is deposited in senile plaques and cerebral blood vessels. However, it is not uncommon to see autopsies that reveal significant deposits of beta-amyloid in the brain without manifesting dementia. In fact, several neuropathological studies showed no correlation between beta-amyloid burden and the severity of dementia or loss of synapses. Thus it is questioned whether extracellularly deposited beta-amyloid is directly linked to the Alzheimer pathomechanism. Here I show evidence to support the significance of intraneuronally deposited A beta x-42 by analyzing presenilin 1 transgenic mice and AD patients.
Alzheimer Disease↗
[Progress in developing anti-Alzheimer drugs].
According to the amyloid hypothesis, accumulation of beta amyloid in the brain seems to be the primary influence driving Alzheimer's disease pathogenesis. From the studies of A beta production, aggregation, degradation and clearance, several strategies for preventing or delaying the disease onset and progression have been postulated. These are beta-secretase inhibitors, gamma-secretase inhibitors, A beta degrading enzymes, anti-cholesterol drugs, non-steroidal anti-inflammatory drugs, beta-sheet breakers, chelating agents, SAP competitors, beta-amyloid vaccination, agents for trapping peripheral A beta, and so on. Here I review recent progress in developing anti-Alzheimer drugs.
Alzheimer Disease↗
Chronic stress impairs rotarod performance in rats: implications for depressive state.
Exposure to chronic stress is thought to precipitate or exacerbate several neuropsychiatric disorders such as depression. Here, we examined the effects of chronic stress administered by water immersion and restraint (2 h/day) for 4 weeks followed by a 10-day recovery period on rotarod performance. The time course study revealed that the riding time on a rotating rod was not affected at Day 1 or Week 1 of the stress period, but was significantly decreased at Week 4 and after the 10-day recovery period. However, traction performance and locomotor activity were not changed by chronic stress. We next examined the involvement of a serotonergic mechanism in the impairment of rotarod performance. The post-stress administration of a serotonergic antidepressant, trazodone (10 mg/kg, daily for 10 days) significantly ameliorated the impairment of rotarod performance. A microdialysis study also revealed a decrease in the extracellular concentration of serotonin in the prefrontal cortex. These results indicate that chronic stress impairs the rotarod performance in a manner that is not due to muscle relaxation or motor dysfunction, and this impairment may imply a behaviorally depressive state mediated by a serotonergic mechanism. These findings provide insight into the underlying mechanisms of stress-induced neuropsychiatric disorders.
Animals↗
Autonomic regulation of experimental autoimmune encephalomyelitis: the role of interferon-gamma.
OBJECTIVE: The effect of chemical sympathectomy on experimental autoimmune encephalomyelitis (EAE) was studied in interferon-gamma (IFN-gamma) knockout C57BL/6 mice. METHODS: Mice were immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide. Sympathectomy was achieved by subcutaneous administration of 6-hydroxydopamine. RESULTS: We showed previously that wild-type mice developed a mild form of EAE with complete recovery. Sympathectomy caused more serious disease and mice did not recover completely, indicating that the sympathetic nervous system (SNS) downmodulates the process of EAE. The clinical signs of disease were more serious in untreated IFN-gamma(-/-) mice than in wild-type animals. Unexpectedly, sympathectomy resulted in suppression of active EAE in IFN-gamma(-/-) mice, implying that control of actively induced EAE by the SNS depends on INF-gamma and the integrity of the cytokine network. We also induced EAE by passive transfer of MOG(35-55)-reactive lymph node cells, and this disease was aggravated by sympathectomy in both wild-type and knockout animals. CONCLUSIONS: Our study supports the idea that the integrity of the whole cytokine network is necessary to maintain normal nervous-immune system interactions.
Animals↗
[A case of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy) with Notch 3 (Arg169Cys) mutation and typical granular osmiophilic materials in peripheral small arteries].
We report a 64-year-old Japanese woman with recurrent ischemic strokes and progressive dementia without any cardiovascular risk factors. Her first stroke was at 45 years old, and she has a family history of ischemic strokes compatible with an autosomal dominant trait. Marked leukoaraiosis and multiple lacunar infarcts were shown on brain MR images, and no atherosclerotic changes were observed in her extra- and intra-cranial arteries by cervical arterial echography and intracranial MR angiography. Excluded other inherited or metabolic diseases causing leukodystrophy by examination of her blood samples, her disease was diagnosed as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy). We demonstrated granular osmiophilic materials (GOM) on the wall of small arteries from a biopsied peripheral nerve tissue specimen and detected a mutation Arg169Cys of Notch 3 gene. Many CADASIL patients have been reported and over 28 kinds of mutations of the Notch 3 were identified in western countries, while few CADASIL patients have been reported in Japanese people. Among them, eleven CADASIL families have been reported and only five mutations (Arg133Cys, Cys174Phe, Arg213Lys, Arg90Cys and Arg141Cys) have been determined so far. The mutation of Notch 3 in our patient was determined as Arg169Cys, and this is the first report on a Japanese patient with CADASIL due to this mutation.
Arteries↗