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Alzheimer&am... more
Alzheimer's disease is characterized by progressive loss of cognitive function due to amyloid-l (Al) deposits in the central nervous system. Based on the amyloid cascade theory, many reports indicated that immunotherapy is effective for the treatment of Alzheimer's disease. We developed a mucosal immunotherapy for Alzheimer's disease via oral vaccine with recombinant adeno-associated virus (AAV) vector and nasal administration of recombinant sendaivirus vector expressing Al 1-43/IL-10. Oral or nasal administration of recombinant virus vector induced the long-term expression of All in the epithelial cells and presented the Ap antigen to the mucosal immune system. Antibody levels in the mouse serum were elevated after 4 weeks and the antibody inhibited the aggregation of Ap in vitro. Immunohistochemistry of the APP transgenic mouse brain tissue showed that All burdens were markedly decreased in the treated mouse compared to the control. The inflammation was not recognized in any organ including brain and kidney. Mucosal immunotherapy with viral vectors significantly cleared the Ap depositions without inflammation and reduced the levels of Al in the brain homogenates of APP transgenic mice; therefore, it might be effective for the treatment of Alzheimer's disease.
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Research Interests: Physiology, Membrane Proteins, RNA interference, Humans, Sequence alignment, and 13 moreMice, Animals, Data Collection, Medical Physiology, Presenilins, Membrane Protein, Brain Chemistry, Gene Family, FASEB J, Biochemistry and cell biology, Gene Expression Regulation, Molecular Sequence Data, and fibroblasts
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This is an abstract of my lecture on familial non-Alzheimer dementia. 1. Vascular dementia 1) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by autosomal dominant... more
This is an abstract of my lecture on familial non-Alzheimer dementia. 1. Vascular dementia 1) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by autosomal dominant inheritance, smooth muscle cell degeneration and granular osmiophilic material (GOM) in arterioles, and Notch 3 mutations. 2) CARASIL This is an autosomal recessive vascular dementia with unknown etiology. 3) Familial amyloid angiopathy Familial cerebral hemorrhage and dementia is caused by mutations in amyloid precursor protein, cystatin c, and Bri genes. 2. Familial non-Alzheimer degenerative dementia 1) Dementia with Lewy bodies This is characterized by Alzheimer like dementia, visual hallucination and diffuse Lewy bodies which are formed by ubiquitinated alpha-synuclein. Occasionally, familial forms are reported, but gene mutations are unknown. 2) Frontotemporal dementia (FTD) FTDP-17 is characterized by tau mutations, character and personal changes, and disinhibition. The gene mutations were also found in familial forms of Pick's disease, corticobasal degeneration, and other tauopathies. 3) Familial British dementia (FBD), familial Danish dementia (FDD) FBD and FDD are characterized by Abri amyloid deposits, amyloid angiopathy and dementia. Mutations in Bri gene are reported. 4) Familial encephalopathy with neuroserpin inclusion bodies (FENIB) FENIB is characterized by dementia, Collins body and neuroserpin gene mutation.
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ABSTRACT
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Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease. Acceleration of apoptosis is one of the major pathogenic mechanisms of PS1 mutants, and PS1 mutants have also been reported to induce... more
Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease. Acceleration of apoptosis is one of the major pathogenic mechanisms of PS1 mutants, and PS1 mutants have also been reported to induce overproduction of amyloid-beta protein 42. Here, we investigated aberrancy in activation of initiator caspases related to two PS1 gene mutations, I143T and G384A. Acceleration of apoptosis, elevation of caspase-3/7 activity, and significant increases in caspase-4, -8 and -9 activities during apoptosis induced by several agents were found in these mutant PS1-transfected cells. Interestingly, thapsigargin treatment enhanced caspase-4 and -9 activities in I143T-mutant PS1-transfected cells, while hydrogen peroxide treatment enhanced caspase-4, -8 and -9 activities in G384A-mutant PS1-transfected cells, indicating diverse apoptosis-promoting effects of PS1 gene mutations. In addition, treatment with a beta-secretase inhibitor or gamma-secretase inhibito...
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Autopsy cases who had received Abeta vaccine showed clearance of senile plaques, and beneficial effect was shown in patients who had high antibody titers to amyloid plaques. Thus, vaccination is widely accepted as promising therapy for... more
Autopsy cases who had received Abeta vaccine showed clearance of senile plaques, and beneficial effect was shown in patients who had high antibody titers to amyloid plaques. Thus, vaccination is widely accepted as promising therapy for Alzheimer disease. Since active immunization induced autoimmune-like meningoencephalitis, pharmaceutical companies are interested in passive immunization using monoclonal antibodies to Abeta. However, due to immunization burden and economical issues, safe active immunization is still attractive. We developed oral or nasal Abeta vaccine using viral vectors and Abeta cDNA with a signal peptide. These vaccine reduced amyloid burden and improved cognitive functions in mice. We believe this vaccine is useful for prevention and treatment of Alzheimer disease.
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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... more
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 ...
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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.... more
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.
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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... more
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.
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We measured the concentration of neurotransmitters in immortalized neural cell lines of hippocampal, septal, brainstem and cerebellar origin. While in most of the cell lines, concentrations of monoamines, gamma-aminobutyric acid (GABA)... more
We measured the concentration of neurotransmitters in immortalized neural cell lines of hippocampal, septal, brainstem and cerebellar origin. While in most of the cell lines, concentrations of monoamines, gamma-aminobutyric acid (GABA) and acetylcholine were low, in some they were markedly higher. This made it quite easy to identify possible monoaminergic, GABAergic or cholinergic cell lines. However all the cell lines contained glutamate and aspartate and there were no outstanding differences in levels of these amino acids differences between the cell lines. Deprivation of serum, which made the cells acquire a more differentiated morphology, caused an increase in the intracellular concentrations of some compounds and a switch from multiple to a single transmitter in the case of some cell lines. It suggested that measurement of transmitter concentrations combined with serum deprivation studies, may provide an indication of the neurochemical characteristics of immortalised neuronal c...
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Seventeen autopsy cases were collected in the Philippines. Mean age of onset 32.5 years, male/female ratio 1/2, no seasonal change, and the patients' occupation variable. A half had prodromal symptoms: mild fever, general malaise and... more
Seventeen autopsy cases were collected in the Philippines. Mean age of onset 32.5 years, male/female ratio 1/2, no seasonal change, and the patients' occupation variable. A half had prodromal symptoms: mild fever, general malaise and headache. The disease was characterized by acute onset with behavioral changes, reticence, hemi- or quadriplegia with pyramidal signs, and incontinence. A quarter of patients had generalized seizure. There were no specific abnormalities in the routine blood examination, and CSF showed unexpectedly mild change. CT scan and MRI show diffuse or multifocal abnormalities in the centrum semiovale. They died of cerebral herniation or secondary infection. The brain was characterized by diffuse or multifocal necrotic and concentric demyelination in the cerebral white matter with marked gemistocytosis.
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We examined the effects of interleukin-3 (IL-3) and other hematopoietic cytokines on the neurotransmitters, neurite formation, and differentiation in cholinergic and other types of neurons. IL-3, granulocyte-macrophage colony-stimulating... more
We examined the effects of interleukin-3 (IL-3) and other hematopoietic cytokines on the neurotransmitters, neurite formation, and differentiation in cholinergic and other types of neurons. IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor, granulocyte colony-stimulating factor and erythropoietin (Epo) elevated choline acetyltransferase (ChAT) activity in septal cholinergic cell line SN6 as well as in primary cultured septal neurons without increasing protein contents of the cells. These effects were dose-dependent and the optimal doses were not different from those for blood cells. IL-3 had neurite-promoting activity but GM-CSF had no such effect. Both IL-3 and GM-CSF decreased intracellular acetylcholine concentration, and elevated glutamic acid decarboxylase and intracellular GABA in septal neuronal cultures. Epo elevated monoamines in PC12 cells. These effects are thought to result from direct action through their specific rece...
Research Interests: Cognitive Science, Developmental neuroscience, Immunohistochemistry, Erythropoietin, Cell line, and 15 moreHumans, Mice, Animals, Acetylcholine, Neurons, Fibroblast Growth Factor, Immune system, LIF, Nervous System, Base Sequence, Growth Factor, Blood cells, Choline Acetyltransferase, Molecular Sequence Data, and DMEM
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... 1982 Aug;22(8):718-24. [Lipidosis with vertical gaze palsy, macular degeneration, and sphingomyelinase deficiency]. [Article in Japanese]. Machi M, Tabira T, Shibasaki H, Goto I, Kuroiwa Y. PMID: 6295677 [PubMed - indexed for... more
... 1982 Aug;22(8):718-24. [Lipidosis with vertical gaze palsy, macular degeneration, and sphingomyelinase deficiency]. [Article in Japanese]. Machi M, Tabira T, Shibasaki H, Goto I, Kuroiwa Y. PMID: 6295677 [PubMed - indexed for MEDLINE]. Publication Types: ...
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We reported a case of late infantile neuronal ceroid-lipofuscinosis. The patient was an 8-year-old boy presenting with marked psychomotor deterioration, progressive visual failure due to retinal degeneration and optic atrophy, startle... more
We reported a case of late infantile neuronal ceroid-lipofuscinosis. The patient was an 8-year-old boy presenting with marked psychomotor deterioration, progressive visual failure due to retinal degeneration and optic atrophy, startle reaction to auditory stimuli, frequent myoclonus and generalized convulsions. The routine laboratory examinations were all normal. EEG was markedly abnormal because of poorly organized background activity and frequent paroxysmal spike-and-wave complexes. CT scan showed evidence of severe atrophy of the cerebrum, cerebellum and brainstem. Electron microscopic examination of the biopsied rectum revealed fingerprint profiles in the neurons and pericytes beneath the muscularis mucosa. Cultured skin fibroblasts also contained electron dense inclusions, some of which showed fingerprint profiles. Urinary glycopeptides were normal. Lyscsomal enzyme activities in leukocytes and cultured fibroblasts were normal. Neurophysiological studies revealed giant cortical...
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In order to obtain a clue to understand the induction mechanism of chronic form of EAE we studied the immunized site of EAE animals with immunocytochemical techniques. There were numerous vacuoles associated with inflammatory reactions in... more
In order to obtain a clue to understand the induction mechanism of chronic form of EAE we studied the immunized site of EAE animals with immunocytochemical techniques. There were numerous vacuoles associated with inflammatory reactions in the subcutaneous tissue of immunized feet. Immunocytochemical staining with antiserum to myelin basic protein (MBP) disclosed remaining of MBP in and around the vacuoles. The MBP remained more in early stage and less in chronic stage; it remained even on 326th day of postimmunization. A possible role of the remained antigen in chronic EAE was discussed.
Research Interests: Pain, Japan, Humans, Male, Pedigree, and 5 moreClinical Sciences, Adult, Carbamazepine, Glycolipids, and Syndrome
Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS). Its immune mechanism is well understood at the cellular and molecular levels, which is herein reviewed. Susceptibility to EAE is... more
Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS). Its immune mechanism is well understood at the cellular and molecular levels, which is herein reviewed. Susceptibility to EAE is under the control of the genes partially inside and partially outside the H-2 complex. There are two myelin constituents known to be encephalitogenic, myelin basic protein and proteolipid apoprotein. EAE is mediated by effector T cells sensitized to the encephalitogen. Effector T cells bear surface phenotypes of Lyt1+2-, L3T4+, and they are activated by the encephalitogen/self Ia complex or certain alloantigens and acquire encephalitogenic activity. By unknown homing mechanisms, the effector T cells invade the CNS and induce the target phase phenomena, which include Ia-antigen expression in the local tissue, activation of procoagulant activity, breakdown of the blood-brain barrier, and excretion of lymphokines which induce inflammation and demyelinat...
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Based on the amyloid cascade hypothesis, immunotherapy targeting amyloid β (Aβ) for Alzheimer's disease (AD) has been developed. It was reported that active immunization using Aβ peptide attenuates amyloid deposits and memory... more
Based on the amyloid cascade hypothesis, immunotherapy targeting amyloid β (Aβ) for Alzheimer's disease (AD) has been developed. It was reported that active immunization using Aβ peptide attenuates amyloid deposits and memory impairment in AD model mice. However, active immunization of patients with AD (AN-1792) was halted due to adverse effects in which a subset of patients developed meningoencephalitis. In order to avoid autoimmune encephalitis, passive immunotherapy using humanized monoclonal antibodies with specificity to Aβ are in clinical trials. We also developed an anti-Aβ monoclonal antibody 3.4A10, which react with AD brain-specific Aβ oligomers. On the other hand, some studies showed that immunotherapy approach targeting tau could attenuate pathology in AD model mouse. Here we introduce a current trend of immunotherapy for AD.
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Excess manganese (Mn) in brain can be neurotoxic, implicated in several neurodegenerative disorders such as sporadic Alzheimer's disease (AD). However, little is known about the altered metal environment including elevated Mn in the... more
Excess manganese (Mn) in brain can be neurotoxic, implicated in several neurodegenerative disorders such as sporadic Alzheimer's disease (AD). However, little is known about the altered metal environment including elevated Mn in the progressive cognitive impairment of AD. Indeed, whether high Mn is associated with AD risk remains elusive. In the study, we recruited 40 Chinese elders with different cognitive statuses and investigated concentrations of Mn in whole blood and plasma amyloid-β (Aβ) peptides. Surprisingly, there were significant correlations of Mn with Mini-Mental State Examination score and Clinical Dementia Rating Scale score. In addition, plasma Aβ peptides increased with elevated Mn. Further studies both in vitro and in vivo demonstrated dose-related neurotoxicity and increase of Aβ by Mn treatment, which was probably caused by disrupted Aβ degradation. These data suggested that high Mn may be involved in the progress of AD as an essential pathogenic factor.
Research Interests: Cognitive Science, Manganese, Brain, Humans, Mutation, and 15 moreMice, Female, Animals, Male, Clinical Sciences, Neuroblastoma, Aged, Exploratory Behavior, Alzheimer Disease, Maze Learning, Neurosciences, Cognition disorders, Gene Expression Regulation, Case Control Studies, and Amyloid Beta Precursor Protein
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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... more
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 mu...
Research Interests: Psychology, Dementia, Poland, Humans, Aged, and 5 morePrevalence, Middle Aged, Genetic variation, Neurosciences, and Tau proteins
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... more
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 th...