11 results on '"Ohtsuki, Sumio"'
Search Results
2. Involvement of Insulin-Degrading Enzyme in Insulin- and Atrial Natriuretic Peptide-Sensitive Internalization of Amyloid-β Peptide in Mouse Brain Capillary Endothelial Cells.
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Ito, Shingo, Ohtsuki, Sumio, Murata, Sho, Katsukura, Yuki, Suzuki, Hiroya, Funaki, Miho, Tachikawa, Masanori, and Terasaki, Tetsuya
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ALZHEIMER'S disease research , *BLOOD-brain barrier , *INSULIN research , *ATRIAL natriuretic peptides , *ENDOTHELIAL cells , *BRAIN research , *ANIMAL models in research - Abstract
Cerebral clearance of amyloid-β peptide (Aβ), which is implicated in Alzheimer's disease, involves elimination across the blood-brain barrier (BBB), and we previously showed that an insulin-sensitive process is involved in the case of Aβ1-40. The purpose of this study was to clarify the molecular mechanism of the insulin-sensitive Aβ1-40 elimination across mouse BBB. An in vivo cerebral microinjection study demonstrated that [125I]hAβ1-40 elimination from mouse brain was inhibited by human natriuretic peptide (hANP), and [125I]hANP elimination was inhibited by hAβ1-40, suggesting that hAβ1-40 and hANP share a common elimination process. Internalization of [125I]hAβ1-40 into cultured mouse brain capillary endothelial cells (TM-BBB4) was significantly inhibited by either insulin, hANP, other natriuretic peptides or insulin-degrading enzyme (IDE) inhibitors, but was not inhibited by phosphoramidon or thiorphan. Although we have reported the involvement of natriuretic peptide receptor C (Npr-C) in hANP internalization, cells stably expressing Npr-C internalized [125I]hANP but not [125I]hAβ1-40, suggesting that there is no direct interaction between Npr-C and hAβ1-40. IDE was detected in plasma membrane of TM-BBB4 cells, and internalization of [125I]hAβ1-40 by TM-BBB4 cells was reduced by IDE-targeted siRNAs. We conclude that elimination of hAβ1-40 from mouse brain across the BBB involves an insulin- and ANP-sensitive process, mediated by IDE expressed in brain capillary endothelial cells. [ABSTRACT FROM AUTHOR]
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- 2014
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3. Amyloid-β peptide(1-40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier.
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Fujiyoshi, Masachika, Tachikawa, Masanori, Ohtsuki, Sumio, Ito, Shingo, Uchida, Yasuo, Akanuma, Shin-ichi, Kamiie, Junichi, Hashimoto, Tadafumi, Hosoya, Ken-ichi, Iwatsubo, Takeshi, and Terasaki, Tetsuya
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AMYLOID ,CEREBROSPINAL fluid ,LOW density lipoproteins ,ALZHEIMER'S disease ,EPITHELIAL cells ,CELL lines - Abstract
Amyloid-β peptide (Aβ) concentration in CSF is potentially a diagnostic and therapeutic target for Alzheimer's disease (AD). The purpose of this study was to clarify the elimination mechanism of human Aβ(1-40) [hAβ (1-40)] from CSF. After intracerebroventricular (ICV) administration, [
125 I]hAβ(1-40) was eliminated from the rat CSF with a half-life of 17.3 min. The elimination of [125 I]hAβ(1-40) was significantly inhibited by human receptor-associated protein (RAP) and the elimination was attenuated in either anti-low-density lipoprotein receptorrelated protein (LRP)1 antibody-treated or RAP-deficient mice, suggesting that a member(s) of the low-density lipoprotein receptor gene family is involved in the elimination of hAβ(1-40) from CSF. The amounts of LRP1 and LRP2 proteins were determined by means of liquid chromatography-tandem mass spectrometry, and the LRP1 content in rat choroid plexus was determined to be 3.7 fmol/μg protein, whereas the LRP2 content was below the detection limit (< 0.2 fmol/μg protein). Conditionally, immortalized rat choroid plexus epithelial cells exhibited predominant apical-to-basal and apical-to-cell transport of [125 I]hAβ(1-40). These results indicated that hAβ(1-40) is actively eliminated from CSF and this process is at least partly mediated by LRP1 expressed at choroid plexus epithelial cells, which therefore play a role in determining CSF concentrations of hAβ(1-40). [ABSTRACT FROM AUTHOR]- Published
- 2011
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4. Establishment of a new conditionally immortalized human brain microvascular endothelial cell line retaining an in vivo blood–brain barrier function.
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SANO, YASUTERU, SHIMIZU, FUMITAKA, ABE, MASAAKI, MAEDA, TOSHIHIKO, KASHIWAMURA, YOKO, OHTSUKI, SUMIO, TERASAKI, TETSUYA, OBINATA, MASUO, KAJIWARA, KOJI, FUJII, MASAMI, SUZUKI, MICHIYASU, and KANDA, TAKASHI
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ENDOTHELIUM ,CEREBRAL ischemia ,ALZHEIMER'S disease ,GLYCOPROTEINS ,INULIN - Abstract
The breakdown of the blood–brain barrier (BBB) has been considered to be a key step in the disease process of a number of neurological disorders such as cerebral ischemia and Alzheimer's disease. Many in vitro BBB models derived from animal tissues have been established to elucidate the mechanism of BBB insufficiency. However, only a few human immortalized in vitro BBB models have been reported. In the present study, a temperature-sensitive SV40-T antigen was introduced to immortalize cells using a retrovirus to obtain a better human in vitro BBB model which sustains physiological properties. This endothelial cell (EC) line, termed TY08, showed a spindle-shaped morphology. The cells expressed all key tight junctional proteins, such as occludin, claudin-5, zonula occludens (ZO)-1 and ZO-2 at their cell-to-cell boundaries, and had low permeability to inulin across its monolayer. The cells also expressed various influx and efflux transporters and exhibited the functional expression of p-glycoprotein. Furthermore, the TY08 cells grew and proliferated well under the permissive temperature and stopped growing under the non-permissive temperature to serve as physiological ECs forming the BBB. Thus, conditionally immortalized TY08 cells retaining the in vivo BBB functions should facilitate analyses for determining the pathophysiology of various neurological diseases. J. Cell. Physiol. 225: 519–528, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
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- 2010
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5. Lack of brain-to-blood efflux transport activity of low-density lipoprotein receptor-related protein-1 (LRP-1) for amyloid-β peptide(1–40) in mouse: involvement of an LRP-1-independent pathway.
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Ito, Shingo, Ueno, Takashi, Ohtsuki, Sumio, and Terasaki, Tetsuya
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LIPOPROTEINS ,NUCLEAR reactions ,CEREBROSPINAL fluid ,VETERINARY drugs ,KETAMINE - Abstract
J. Neurochem. (2010) 113, 1356–1363. The contribution of low-density lipoprotein receptor-related protein-1 (LRP-1) to the brain-to-blood amyloid-β peptide (Aβ) efflux transport across the blood-brain barrier (BBB) remains controversial. The purpose of the present study was to clarify whether or not LRP-1 plays a role in efflux transport of Aβ at the BBB. After microinjection of [
125 I]activated α2-macroglobulin (α2M), a typical LRP-1 ligand, into mouse secondary somatosensory cortex region under ketamine-xylazine anesthesia, residual radioactivity was not significantly decreased up to 90 min, whereas after microinjection of [125 I]human Aβ(1–40) [hAβ(1–40)], the residual radioactivity decreased time-dependently. Co-administration of receptor-associated protein, an inhibitor of LRP-1, did not influence [125 I]hAβ(1–40) elimination from mouse brain, suggesting that members of the LDL receptor gene family, including LRP-1, do not contribute to hAβ(1–40) elimination from mouse brain across the BBB. There was no significant difference between the uptakes of [125 I]activated α2M and [14 C]inulin by mouse brain slices, suggesting that activated α2M was not significantly bound to and/or taken up by parenchymal cells. In conclusion, our results show that LRP-1 does not play a significant role in the brain-to-blood efflux transport of Aβ(1–40) at the mouse BBB, but an unidentified transporter(s) appears to be involved. [ABSTRACT FROM AUTHOR]- Published
- 2010
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6. Aß Immunotherapy: Intracerebral Sequestration of Aß by an Anti-Aß Monoclonal Antibody 266 with High Affinity to Soluble Aß.
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Yamada, Kaoru, Yabuki, Chiori, Seubert, Peter, Schenk, Dale, Hori, Yukiko, Ohtsuki, Sumio, Terasaki, Tetsuya, Hashimoto, Tadafumi, and Iwatsubo, Takeshi
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ALZHEIMER'S disease ,IMMUNOTHERAPY ,NEUROLOGICAL disorders ,NEUROSCIENCES ,IMMUNOGLOBULINS - Abstract
Amyloidβ (Aβ) immunotherapy is emerging as a promising disease-modifying therapy for Alzheimer's disease, although the precise mechanisms whereby anti-Aβ antibodies act against a myloid deposition and cognitive deficits remain elusive. To test the "peripheral sink" theory, which postulates that the effects of anti-Aβantibodies in the systemic circulation are to promote the Aβefflux from brain to blood, we studied the clearance of 125I-Aβ
1-40 microinjected into mouse brains after intraperitoneal administration of an anti-Aβ monoclonal antibody 266. 125I-Aβ1-40 was rapidly eliminated from brains with a half-life of ~30 min in control mice, whereas 266 significantly retarded the elimination of Aβ, presumably due to formation of Aβ-antibody complex in brains. Administration of 266 to APP transgenic mice increased the levels of monomer Aβ species in an antibody-bound form, without affecting that of total Aβ. We propose a novel mechanism of Aβ immunotherapy by the class of anti-Aβ antibodies that preferentially bind soluble Aβ, i.e., intracerebral, rather than peripheral, sequestration of soluble, monomer form of Aβ, thereby preventing the accumulation of multimeric toxic Aβ species in brains. [ABSTRACT FROM AUTHOR]- Published
- 2009
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7. ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-β peptide (1–40) at the blood–brain barrier
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Akanuma, Shin-ichi, Ohtsuki, Sumio, Doi, Youko, Tachikawa, Masanori, Ito, Shingo, Hori, Satoko, Asashima, Tomoko, Hashimoto, Tadafumi, Yamada, Kaoru, Ueda, Kazumitsu, Iwatsubo, Takeshi, and Terasaki, Tetsuya
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SYSTEMIC memory hypothesis , *MICE , *ANIMAL models in research , *MEDICAL research - Abstract
Abstract: ATP-binding cassette transporter A1 (ABCA1) mediates apolipoprotein-dependent cholesterol release from cellular membranes. Recent studies using ABCA1 knockout mice have demonstrated that ABCA1 affects amyloid-β peptide (Aβ) levels in the brain and the production of senile plaque. Cerebral Aβ(1–40) was eliminated from the brain to the circulating blood via the blood–brain barrier (BBB), which expresses ABCA1. Therefore, in the present study, we examined whether ABCA1 affects the brain-to-blood efflux transport of human Aβ(1–40)(hAβ(1–40)) at the BBB. The apparent uptake of [125I]hAβ(1–40) into ABCA1-expressing HEK293 cells was not significantly different from that into parental HEK293 cells. In addition, the apparent uptake was not significantly affected even in the presence of apolipoprotein A–I as a cholesterol release acceptor. Moreover, [125I]hAβ(1–40) elimination from mouse brain across the BBB was not significantly different between ABCA1-deficient and wild-type mice 60min after its administration into the cerebrum. These results suggest that ABCA1 does not directly transport hAβ(1–40) and a deficiency of ABCA1 does not attenuate the brain-to-blood efflux transport of hAβ(1–40) across the BBB. [Copyright &y& Elsevier]
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- 2008
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8. Cerebral clearance of human amyloid-β peptide (1–40) across the blood–brain barrier is reduced by self-aggregation and formation of low-density lipoprotein receptor-related protein-1 ligand complexes.
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Ito, Shingo, Ohtsuki, Sumio, Kamiie, Junichi, Nezu, Yasuko, and Terasaki, Tetsuya
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APOLIPOPROTEIN E , *OLIGOMERS , *APOPTOSIS , *CELL death , *CYSTEINE proteinases , *CALPAIN , *CEREBRAL cortex , *AUTOIMMUNE diseases - Abstract
Soluble amyloid-β peptide (Aβ) exists in the form of monomers and oligomers, and as complexes with Aβ-binding molecules, such as low-density lipoprotein receptor-related protein-1 (LRP-1) ligands. The present study investigated the effect of self-aggregation and LRP-1 ligands on the elimination of human Aβ(1–40) [hAβ(1–40)] from the rat brain across the blood–brain barrier. Incubation of [125I]hAβ(1–40) monomer resulted in time-dependent and temperature-dependent dimer formation, and the apparent elimination rate of [125I]hAβ(1–40) dimer was significantly decreased by 92.7% compared with that of [125I]hAβ(1–40) monomer. Pre-incubation with LRP-1 ligands, such as activated α2-macroglobulin (α2M), apolipoprotein E2 (apoE2), apoE3, apoE4, and lactoferrin, reduced the elimination of [125I]hAβ(1–40). By contrast, pre-administration of the same concentration of these molecules in the rat brain did not significantly inhibit [125I]hAβ(1–40) monomer elimination. Purified [125I]hAβ(1–40)/activated α2M complex and [125I]activated α2M were not significantly eliminated from the rat brain up to 60 min. MEF-1 cells, which have LRP-1-mediated endocytosis, exhibited uptake of [125I]activated α2M, and enhancement of [125I]hAβ(1–40) uptake upon pre-incubation with apoE, suggesting that [125I]activated α2M and [125I]hAβ(1–40)/apoE complex function as LRP-1 ligands. These findings indicate that dimerization and LRP-1-ligand complex formation prevent the elimination of hAβ(1–40) from the brain across the blood–brain barrier. [ABSTRACT FROM AUTHOR]
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- 2007
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9. Functional characterization of the brain-to-blood efflux clearance of human amyloid-β peptide (1–40) across the rat blood–brain barrier
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Ito, Shingo, Ohtsuki, Sumio, and Terasaki, Tetsuya
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PEPTIDES , *GLYCOPROTEINS , *ENZYMES , *LABORATORY rats - Abstract
Abstract: The present study sought to characterize the brain-to-blood efflux transport of human amyloid-β peptide (hAβ)(1–40) across the blood–brain barrier (BBB) in rats. We determined the apparent brain-to-blood [125I]hAβ(1–40) efflux clearance in rats and found it to be 11.0μL/(ming brain). There were no significant gender differences in the apparent brain-to-blood [125I]hAβ(1–40) efflux clearance. The brain-to-blood [125I]hAβ(1–40) efflux transport was significantly inhibited by unlabeled hAβ(1–40) and hAβ(1–42) by 79.1% and 36.4%, respectively, but was not inhibited by hAβ(1–43) and hAβ(40–1), and was significantly facilitated by hAβ(17–40) by 16.0%, which is one of the major proteolytic fragments of hAβ(1–40) generated by the action of Aβ degradation enzymes, such as endothelin-converting enzyme. Pre-administration of human receptor-associated protein, a low-density lipoprotein receptor-related protein (LRP) antagonist, reduced the elimination of [125I]hAβ(1–40) by 20.3%, while quinidine or verapamil, P-glycoprotein (P-gp) inhibitors, did not significantly affect the elimination. Western blot analysis suggested that LRP-1 is expressed in rat brain capillary endothelial cells. In conclusion, the partial contribution of LRP-1 and the minor contribution of P-gp suggest that the hAβ(1–40) elimination from rat brain is mediated by as yet unidentified molecules. [Copyright &y& Elsevier]
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- 2006
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10. Brain Insulin Impairs Amyloid-β(1-40) Clearance from the Brain.
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Shiiki, Takeshi, Ohtsuki, Sumio, Kurihara, Atsushi, Naganuma, Hideo, Nishimura, Kenji, Tachikawa, Masanori, Hosoya, Ken-ichi, and Terasaki, Tetsuya
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BRAIN , *INSULIN , *PEPTIDES , *ENZYMES , *BACITRACIN - Abstract
Cerebral amyloid-β peptide (Aβ) clearance plays a key role in determining the brain level of Aβ; however, its mechanism remains unclear. In this study, we investigated cerebral Aβ clearance across the blood-brain barrier (BBB) by using the Brain Efflux Index method. [125I]Aβ(1- 40) was eliminated from rat brain to circulating blood with a half-life of 48.8 min and a half-saturation concentration of 8.15 nM. The Aβ (1-40) elimination rate was reduced by 30.5% in 23-month-old rats compared with 7-week-old rats. The intact form of Aβ(1-40) was detected in plasma after intracerebral administration, indicating the occurrence of efflux transport of intact Aβ (1-40). The Aβ (1-40) elimination rate was significantly inhibited by coadministration of 100 µg/ml insulin and 1 mM thiorphan by 44.6 and 34.0%, respectively. The level of intact [125I]Aβ(1-40) in the brain was increased by coadministration of insulin. Among insulindegrading enzyme inhibitors, bacitracin inhibited the elimination rate, whereas N-ethylmaleimide and metal chelators had no effect. Receptor-associated protein, fucoidan, 3-bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile, anti-IGF-I receptor antibody, and L-tyrosine did not affect the Aβ (1-40) elimination rate, suggesting that the relevant receptors or transporters are not likely to be involved in the clearance. In conclusion, the present study has demonstrated the involvement of a proteolytic degradation process and an insulinsensitive process in cerebral Aβ(1-40) clearance in the rat. [ABSTRACT FROM AUTHOR]
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- 2004
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11. The Low Density Lipoprotein Receptor-related Protein 1 Mediates Uptake of Amyloid β Peptides in an in Vitro Model of the Blood-Brain Barrier Cells.
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Yamada, Kaoru, Hashimoto, Tadafumi, Yabuki, Chiori, Nagae, Yusuke, Tachikawa, Masanori, Strickland, Dudley K., Qiang Liu, Guojun Bu, Basak, Jacob M., Holtzman, David M., Ohtsuki, Sumio, Terasaki, Tetsuya, and Iwatsubo, Takeshi
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ALZHEIMER'S disease , *AMYLOID , *METABOLISM , *BLOOD-brain barrier , *LIPOPROTEINS , *FIBROBLASTS , *RNA - Abstract
The metabolism of amyloid β peptide (Aβ) in the brain is crucial to the pathogenesis of Alzheimer disease. A body of evidence suggests that Aβ is actively transported from brain parenchyma to blood across the blood-brain barrier (BBB), although the precise mechanism remains unclear. To unravel the cellular and molecular mechanism of Aβ transport across the BBB, we established a new in vitro model of the initial internalization step of Aβ transport using TR-BBB cells, a conditionally immortalized endothelial cell line from rat brain. We show that TR-BBB cells rapidly internalize Aβ through a receptor-mediated mechanism. We also provide evidence that Aβ internalization is mediated by LRP1 (low density lipoprotein receptor-related protein 1), since administration of LRP1 antagonist, receptor-associated protein, neutralizing antibody, or small interference RNAs all reduced Aβ uptake. Despite the requirement of LRP1-dependent internalization, Aβ does not directly bind to LRP1 in an in vitro binding assay. Unlike TR-BBB cells, mouse embryonic fibroblasts endogenously expressing functional LRP1 and exhibiting the authentic LRP1-mediated endocytosis (e.g. of tissue plasminogen activator) did not show rapid Aβ uptake. Based on these data, we propose that the rapid LRP 1-dependent internalization of Aβ occurs under the BBB-specific cellular context and that TR-BBB is a useful tool for analyzing the molecular mechanism of the rapid transport of Aβ across BBB. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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