Takami Tomiyama
Osaka City University
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Featured researches published by Takami Tomiyama.
Annals of Neurology | 2008
Takami Tomiyama; Tetsu Nagata; Hiroyuki Shimada; Rie Teraoka; Akiko Fukushima; Hyoue Kanemitsu; Hiroshi Takuma; Ryozo Kuwano; Masaki Imagawa; Suzuka Ataka; Eito Yoshioka; Tomoyuki Nishizaki; Yasuyoshi Watanabe; Hiroshi Mori
Soluble oligomers of amyloid β (Aβ), rather than amyloid fibrils, have been proposed to initiate synaptic and cognitive dysfunction in Alzheimers disease (AD). However, there is no direct evidence in humans that this mechanism can cause AD. Here, we report a novel amyloid precursor protein (APP) mutation that may provide evidence to address this question.
The Journal of Neuroscience | 2010
Takami Tomiyama; Shogo Matsuyama; Hiroyuki Iso; Tomohiro Umeda; Hiroshi Takuma; Kiyouhisa Ohnishi; Kenichi Ishibashi; Rie Teraoka; Naomi Sakama; Takenari Yamashita; Kazuchika Nishitsuji; Kazuhiro Ito; Hiroyuki Shimada; Mary P. Lambert; William L. Klein; Hiroshi Mori
Although amyloid β (Aβ) oligomers are presumed to cause synaptic and cognitive dysfunction in Alzheimers disease (AD), their contribution to other pathological features of AD remains unclear. To address the latter, we generated APP transgenic mice expressing the E693Δ mutation, which causes AD by enhanced Aβ oligomerization without fibrillization. The mice displayed age-dependent accumulation of intraneuronal Aβ oligomers from 8 months but no extracellular amyloid deposits even at 24 months. Hippocampal synaptic plasticity and memory were impaired at 8 months, at which time the presynaptic marker synaptophysin began to decrease. Furthermore, we detected abnormal tau phosphorylation from 8 months, microglial activation from 12 months, astrocyte activation from 18 months, and neuronal loss at 24 months. These findings suggest that Aβ oligomers cause not only synaptic alteration but also other features of AD pathology and that these mice are a useful model of Aβ oligomer-induced pathology in the absence of amyloid plaques.
The Journal of Neuroscience | 2007
Jun Maeda; Bin Ji; Toshiaki Irie; Takami Tomiyama; Masahiro Maruyama; Takashi Okauchi; Matthias Staufenbiel; Nobuhisa Iwata; Maiko Ono; Takaomi C. Saido; Kazutoshi Suzuki; Hiroshi Mori; Makoto Higuchi; Tetsuya Suhara
We provide the first evidence for the capability of a high-resolution positron emission tomographic (PET) imaging system in quantitatively mapping amyloid accumulation in living amyloid precursor protein transgenic (Tg) mice. After the intravenous administration of N-[11C]methyl-2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (or [11C]PIB for “Pittsburgh Compound-B”) with high-specific radioactivity, the Tg mice exhibited high-level retention of radioactivity in amyloid-rich regions. PET investigation for Tg mice over an extended range of ages, including longitudinal assessments, demonstrated age-dependent increase in radioligand binding consistent with progressive amyloid accumulation. Reduction in amyloid levels in the hippocampus of Tg mice was also successfully monitored by multiple PET scans along the time course of anti-amyloid treatment using an antibody against amyloid β peptide (Aβ). Moreover, PET scans with [18F]fluoroethyl-DAA1106, a radiotracer for activated glia, were conducted for these individuals parallel to amyloid imaging, revealing treatment-induced neuroinflammatory responses, the magnitude of which intimately correlated with the levels of pre-existing amyloid estimated by [11C]PIB. It is also noteworthy that the localization and abundance of [11C]PIB autoradiographic signals were closely associated with those of N-terminally truncated and modified Aβ, AβN3-pyroglutamate, in Alzheimers disease (AD) and Tg mouse brains, implying that the detectability of amyloid by [11C]PIB positron emission tomography is dependent on the accumulation of specific Aβ subtypes. Our results support the usefulness of the small animal-dedicated PET system in conjunction with high-specific radioactivity probes and appropriate Tg models not only for clarifying the mechanistic properties of amyloidogenesis in mouse models but also for preclinical tests of emerging diagnostic and therapeutic approaches to AD.
Journal of Biological Chemistry | 1996
Takami Tomiyama; Akira Shoji; Kenichiro Kataoka; Yorimasa Suwa; Satoshi Asano; Hideshi Kaneko; Noriaki Endo
Aggregation of physiologically produced soluble amyloid β protein (Aβ) to insoluble, neurotoxic fibrils is a crucial step in the pathogenesis of Alzheimers disease. Aggregation studies with synthetic Aβ1-40 peptide by the thioflavin T fluorescence assay and electron microscopy and cytotoxicity assays using rat pheochromocytoma PC12 cells showed that an antibiotic, rifampicin, and its derivatives, which possess a naphthohydroquinone or naphthoquinone structure, inhibited Aβ1-40 aggregation and neurotoxicity in a concentration-dependent manner. Hydroquinone, p-benzoquinone, and 1,4dihydroxynaphthalene, which represent partial structures of the aromatic chromophore of rifampicin derivatives, also inhibited Aβ1-40 aggregation and neurotoxicity at comparable molar concentrations to rifampicin. Electron spin resonance spectrometric analysis revealed that the inhibitory activities of those agents correlated with their radical-scavenging ability on hydroxyl free radical, which was shown to be generated in cell-free incubation of Aβ1-40 peptide. These results suggest that at least one mechanism of rifampicin-mediated inhibition of Aβ aggregation and neurotoxicity involves scavenging of free radicals and that rifampicin and/or appropriate hydroxyl radical scavengers may have therapeutic potential for Alzheimers disease.
Neuroscience Letters | 2003
Hyoe Kanemitsu; Takami Tomiyama; Hiroshi Mori
Amyloid beta-peptide (Abeta) is widely believed to play a central role in Alzheimers disease (AD). Coordinate regulation of cerebral Abeta level is important in the pathogenesis of AD since either increased production of Abeta from amyloid precursor protein or decreased degradation causes elevated levels of Abeta, leading to accumulation of cerebral plaque formation or amyloid angiopathy. Here we studied neprilysin, a putative proteolytic enzyme for Abeta, and found that it degraded not only monomeric but also oligomeric forms of Abeta1-40. Moreover, neprilysin was found to be capable of degradation of the oligomeric form of Abeta1-42, a significant Abeta species in early pathogenesis. Neprilysin to decrease cerebral Abeta is suggested to be inevitable factor as a vital therapeutic target.
The Journal of Neuroscience | 2006
Karin Boekhoorn; Dick Terwel; Barbara Biemans; Peter Borghgraef; Olof Wiegert; Ger J. A. Ramakers; Koos de Vos; Harm J. Krugers; Takami Tomiyama; Hiroshi Mori; Marian Joëls; Fred Van Leuven; Paul J. Lucassen
The microtubule binding protein tau is implicated in neurodegenerative tauopathies, including frontotemporal dementia (FTD) with Parkinsonism caused by diverse mutations in the tau gene. Hyperphosphorylation of tau is considered crucial in the age-related formation of neurofibrillary tangles (NFTs) correlating well with neurotoxicity and cognitive defects. Transgenic mice expressing FTD mutant tau-P301L recapitulate the human pathology with progressive neuronal impairment and accumulation of NFT. Here, we studied tau-P301L mice for parameters of learning and memory at a young age, before hyperphosphorylation and tauopathy were apparent. Unexpectedly, in young tau-P301L mice, increased long-term potentiation in the dentate gyrus was observed in parallel with improved cognitive performance in object recognition tests. Neither tau phosphorylation, neurogenesis, nor other morphological parameters that were analyzed could account for these cognitive changes. The data demonstrate that learning and memory processes in the hippocampus of young tau-P301L mice are not impaired and actually improved in the absence of marked phosphorylation of human tau. We conclude that protein tau plays an important beneficial role in normal neuronal processes of hippocampal memory, and conversely, that not tau mutations per se, but the ensuing hyperphosphorylation must be critical for cognitive decline in tauopathies.
Journal of Neuroscience Research | 2011
Tomohiro Umeda; Takami Tomiyama; Naomi Sakama; Saya Tanaka; Mary P. Lambert; William L. Klein; Hiroshi Mori
Intraneuronal accumulation of amyloid β (Aβ) is an early pathological change in Alzheimers disease. Previously, we showed that the E693Δ mutation (referred to as the “Osaka” mutation) of amyloid precursor protein (APP) caused intracellular accumulation of Aβ oligomers and apoptosis in transfected COS‐7 cells. We also showed that transgenic mice expressing APPE693Δ (APPOSK) displayed both an age‐dependent accumulation of intraneuronal Aβ oligomers from 8 months of age and apparent neuronal loss in the hippocampus at 24 months of age. These findings indicate that intraneuronal Aβ oligomers cause cell death, but the mechanism of this process remains unclear. Accordingly, here we investigated the subcellular localization and toxicity of intraneuronal Aβ oligomers in APPOSK‐transgenic mice. We found Aβ oligomer accumulation in the endoplasmic reticulum (ER), endosomes/lysosomes, and mitochondria in hippocampal neurons of 22‐month‐old mice. We also detected up‐regulation of Grp78 and HRD1 (an E3 ubiquitin ligase), leakage of cathepsin D from endosomes/lysosomes into cytoplasm, cytochrome c release from mitochondria, and activation of caspase‐3 in the hippocampi of 18‐month‐old mice. Collectively, our findings suggest that intraneuronal Aβ oligomers cause cell death by inducing ER stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo.
American Journal of Pathology | 2009
Kazuchika Nishitsuji; Takami Tomiyama; Kenichi Ishibashi; Kazuhiro Ito; Rie Teraoka; Mary P. Lambert; William L. Klein; Hiroshi Mori
The E693Delta mutation within the amyloid precursor protein (APP) has been suggested to cause dementia via the enhanced formation of synaptotoxic amyloid beta (Abeta) oligomers. However, this mutation markedly decreases Abeta secretion, implying the existence of an additional mechanism of neuronal dysfunction that is independent of extracellular Abeta. We therefore examined the effects of this mutation on both APP processing to produce Abeta as well as subcellular localization and accumulation of Abeta in transfected HEK293 and COS-7 cells. Both beta- and gamma-cleavage of mutant APP increased, indicating a lack of inhibition in Abeta production. Instead, this mutation promoted Abeta accumulation within cells, including the endoplasmic reticulum (ER), Golgi apparatus, early and late endosomes, lysosomes, and autophagosomes, all of which have been proposed as intracellular sites of Abeta generation and/or degradation, suggesting impairment of APP/Abeta trafficking. Notably, the intracellular mutant Abeta was found to predominantly form oligomers. Concomitant with this accumulation, the ER stress markers Grp78 and phosphorylated eIF2alpha were both strongly induced. Furthermore, the activation of caspase-4 and -3 as well as DNA fragmentation were detected in these cells. These results suggest that mutant Abeta induces alteration of Abeta trafficking and subsequent ER stress-induced apoptosis via enhancement of its intracellular oligomerization. Our findings suggest that Abeta oligomers exhibit toxicity in the extracellular space and within the cells themselves.
The Journal of Neuroscience | 2011
Jun Maeda; Ming-Rong Zhang; Takashi Okauchi; Bin Ji; Maiko Ono; Satoko Hattori; Katsushi Kumata; Nobuhisa Iwata; Takaomi C. Saido; John Q. Trojanowski; Virginia M.-Y. Lee; Matthias Staufenbiel; Takami Tomiyama; Hiroshi Mori; Toshimitsu Fukumura; Tetsuya Suhara; Makoto Higuchi
Core pathologies of Alzheimers disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [11C]AC-5216 and [18F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [11C]Pittsburgh Compound-B, to plaques. In these animals, [11C]AC-5216 yielded better TSPO contrasts than [18F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.
American Journal of Pathology | 2003
Yusuke Hashimoto; Takami Tomiyama; Yoshiki Yamano; Hiroshi Mori
Cartilage oligomeric matrix protein (COMP) is a large pentameric extracellular glycoprotein found in cartilage, tendon, and synovium, and plays structural roles in cartilage as the fifth member of the thrombospondin family. Familial mutations in type 3 repeats of COMP are known to cause pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). Although such mutations induce enlarged rough endoplasmic reticulum (rER) as a morphological change, the metabolic trafficking of mutated COMP remains unclear. In transfected COS7 cells, wild-type COMP was rapidly secreted into culture medium, while the great majority of COMP with the type 3 repeats mutation (D472Y) remained in the cells and a small portion of mutated COMP was secreted. This finding was followed up with a confocal study with an antibody specific to COMP, which demonstrated mutated COMP tightly associated with abnormally enlarged rER. Phosphorylated eIF2alpha, an ER stress protein, was expressed as a pathological reaction in virtually all COS7 cells expressing mutated but not wild-type COMP. Moreover, COS7 cells expressing mutated COMP exhibited significantly more apoptotic reaction than those expressing wild-type COMP. Pathological accumulation of COMP in rER and apoptosis in COS7 cells that were induced by the mutation (D472Y) in COMP imply that COMP mutations play a role in the pathogenesis of PSACH.