Research on the mechanism underlying the accelerated senescence in cathepsin D-deficient mice

• Project/Area Number: 17390495
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Kyushu University
• Principal Investigator: NAKANISHI Hiroshi Kyushu University, Faculty of Dental Sciences, Professor (20155774)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥16,520,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥1,320,000); Fiscal Year 2007: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2006: ¥4,400,000 (Direct Cost: ¥4,400,000); Fiscal Year 2005: ¥6,400,000 (Direct Cost: ¥6,400,000)
• Keywords: senescence / nitric oxide / cathepsin D / lysosomal storage / microglia / 酵素補充 / 単核貧食細胞 / 活性酸素種 / GFPトランスジェニックマウス / 未梢血管内注入

Research Abstract

Nitric oxide (NO) and peroxynitrite, which are produced by activated microglia are responsible for accelerated neurodegeneration in cathepsin D-deficient (CD-/-) mice. To elucidate the mechanisms by which microglia are initially activated in CD-/- mice, we analyzed the possible relationship between lysosomal storage and microglial activation. In CD-/- mice, the microglial NO-generating activity that was closely associated with the induction of inducible NO synthase and the cationic amino acid transporter-2 (CAT-2) coincided well with the lysosomal storage of subunit c of mitochondrial FOF1ATPase and the formation of ceroid/lipofuscin. Furthermore, activated microglia, which are often accumulating subunit c and ceroid/lipofuscin, showed proliferation activity and an activation of p38 mitogen-activated protein (MAP) kinase. In the primary cultured microglia, pepstatin A was found to enhance the generation of NO and superoxide anion radicals. In these pepstatin A-treated microglia, both an increased generation of the intracellular reactive oxygen species (ROS) and an activation of p38 MAP kinase were observed. These results suggest that the ceroid/lipofuscin which form in microglia activate the p38 MAP kinase cascade through the increased intracellular generation of ROS in CD-/- mice. The activated p38 MAP kinase cascade then promotes the expression of iNOS and CAT-2, thereby inducing the overproduction of NO.

Research Products

• [Journal Article] Phospholipids modulate superoxide and nitric oxide production by LPS and phorbol 12-myristate-13-acetate-activated microglia (2007)
  • Author(s): Hashioka S, et. al.
  • Journal Title: Neurochemistry International 50 Pages: 499-506
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Phospholipids modulate superoxide and nitric oxide production by lipopolysaccharide and phorbol 12-myristate-13-acetate-activated microglia (2007)
  • Author(s): Hashioka S, et. al.
  • Journal Title: Free Radical Biology and Medicine 42 Pages: 945-954
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Impairment of the microglial responses to the facial berve axotomy in cathepsin S-deficient mice (2007)
  • Author(s): Hao H.P., et. al.
  • Journal Title: Journal of Neuroscience Research 85 Pages: 2196-2206
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice (2007)
  • Author(s): Yamasaki R, et. al.
  • Journal Title: Molecular and Cellular Neuroscience 35 Pages: 573-584
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Involvement of PGE2 released from leptomeningeal cells in increased expression of TGF-β1 in glial cells and cortical neurons during systemic inflammation (2007)
  • Author(s): Wu, Z., Hayashi, Y., Zhang, J., Nakanishi, H
  • Journal Title: J. Neurosci. Res 85 Pages: 184-192
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Phospholipids modulate superoxide and nitric oxide production by lipopolysaccharide and phorbol 12-myristate-13-acetate-activated microglia (2007)
  • Author(s): Hashioka, S., Han, Y-H., Fujii, S., Kato, H., Monji, A., Utsumi, H., Sawada, M., Nakanishi. H., Kanba, S
  • Journal Title: Neurochem. Int 50 Pages: 499-506
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Phosphatidylserine and phosphatidylcholine-containing liposomes inhibit amyloid β and interferon-γ-induced microglial activation (2007)
  • Author(s): Hashioka, S., Han, Y-H., Fujii, S., Kato, H., Monji, A., Utsumi, H., Sawada, M., Nakanishi H., Kanba, S
  • Journal Title: Free Rad. Biol. Med 42 Pages: 945-954
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Impairment of the microglial responses to the facial berve axotomy in cathepsin S-deficient mice (2007)
  • Author(s): Hao, H.P., Doh-ura, K., Nakanishi, H
  • Journal Title: J. Neurosci. Res 85 Pages: 2196-2206
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of lysosomal storage- induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice (2007)
  • Author(s): Yamasaki, R., Zhang, J., Koshiishi, I., Sastradipura, D., Suniarti, F., Wu, Z., Peters, C., Schwake, M., Uchiyama, Y., Kira, J.-I., Saftig, P., Utsumi, H., Nakanishi, H
  • Journal Title: Mol. Cell. Neurosci 35 Pages: 573-584
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of PGF_2 released from leptomeningeal cells in increased expression of TGF-β1 in glial cells and cortical neurons during systemic inflammation. (2007)
  • Author(s): Wu Z., et. al.
  • Journal Title: Journal of Neuroscience Research 85 Pages: 184-192
  • Peer Reviewed
• [Journal Article] Phospholipids modulate superoxide and nitric oxide production by lipopolysaccharide and phorbol 12-myristate-13-acetate-activated microglia. (2007)
  • Author(s): Hashioka S., et. al.
  • Journal Title: Neurochemistry International 50 Pages: 499-506
  • Peer Reviewed
• [Journal Article] Phospholipids modulate superoxide and nitric oxide production by lipopolysaccharide and phorbol 12-myristate-13-acetate-activated microalia. (2007)
  • Author(s): Hashioka S., et. al.
  • Journal Title: Free Radical Biology and Medicine 42 Pages: 945-954
  • Peer Reviewed
• [Journal Article] Impairment of the microglial responses to the facial berve axotomy in cathepsin S-deficient mice. (2007)
  • Author(s): Hao H. P., et. al.
  • Journal Title: Journal of Neuroscience Research 85 Pages: 2196-2206
  • Peer Reviewed
• [Journal Article] Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice. (2007)
  • Author(s): Yamasaki R., et. al.
  • Journal Title: Molecular and Cellular Neuroscience 35 Pages: 573-584
  • Peer Reviewed
• [Journal Article] Involvement of PGE_2 released from leptomeningeal cells in increased expression of TGF-β1 in glial cells and cortical neurons during systemic unflammation. (2007)
  • Author(s): Wu, Z.et al.
  • Journal Title: J.Neurosci.Res. 85・1 Pages: 184-192
• [Journal Article] Phospholipids modulate superoxide and nitric oxide production by lipopolysaccharide and phorbol 12-myristae-13-acetate-activated microglia. (2007)
  • Author(s): Hashiok, S. et al.
  • Journal Title: Neurochem.Int. 50・3 Pages: 499-506
• [Journal Article] Phosphatidylserine and phosphatibylcholine-containing liposomes inhibit amyloid β and interferon-y-induced microglial activation. (2007)
  • Author(s): Hashioka, S. et al.
  • Journal Title: Free Radic.Biol.Med. 42・7 Pages: 945-954
• [Journal Article] I Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E_2 production of microglia (2006)
  • Author(s): Zhang J, et. al.
  • Journal Title: Journal of Neuroimmunology 172 Pages: 112-120
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Potentiation of NMDA receptor-medoated responses through ativation of the glycine site by microglia secreting soluble factor (2006)
  • Author(s): Hayashi Y, et. al.
  • Journal Title: Glia 53 Pages: 660-668
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] The infra-arterial injection of microglia protects hippocampal CA1 neurons against global ischemia-induced functional deficits in rats (2006)
  • Author(s): Hayashi Y, et. al.
  • Journal Title: Neuroscience 142 Pages: 87-96
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cell cycle-dependent regulation of kainate-induced inward currents in microglia (2006)
  • Author(s): Yamada J, et. al.
  • Journal Title: Biochem Biophys Res Comun 142 Pages: 87-96
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Involvement of PGE_2 released from leptomeningeal cells in increased expression of TGF-β1 in glial cells and cortical neurons during systemic inflammation (2006)
  • Author(s): Wu Z, et. al.
  • Journal Title: Journal of Neuroscience Research 349 Pages: 913-919
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E_2 production of microglia (2006)
  • Author(s): Zhang, J., Fujii, S., Hashioka, S., Tanaka, Y., Wu, Z., Shiratsuchi, A., Nakanishi, Y., Nakanishi, H
  • Journal Title: J. Neuroimmunol 172 Pages: 112-120
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Potentiation of NMDA receptor-medoated responses through ativation of the glycine site by microglia secreting soluble factor (2006)
  • Author(s): Hayashi, Y., Ishibashi, H., Hashimoto, K., Nakansihi, H
  • Journal Title: Glia 53 Pages: 660-668
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The intra-arterial injection of microglia protects hippocampal CA1 neurons against global ischemia-induced functional deficits in rats (2006)
  • Author(s): Hayashi, Y., Tomimatsu, Y., Suzuki, H., Yamada, J., Yao, H., Kagamiishi, Y., Tateishi, N., Sawada, M., Nakanishi, H
  • Journal Title: Neuroscience 142 Pages: 87-96
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cell cycle-dependent regulation of kainate-induced inward currents in microglia (2006)
  • Author(s): Yamada, J., Sawada, M., Nakanishi, H
  • Journal Title: Biochem. Biophys. Res. Commun 349 Pages: 913-919
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The intra-arterial injection of microglia protects hippocampal CA1 neurns against global ischemia-induced functional deficits in rats. (2006)
  • Author(s): Hayashi, Y. et al.
  • Journal Title: Neuroscience 142・1 Pages: 87-96
• [Journal Article] Cell cycle-dependent regulation of kainite-induced inward currents in microglia. (2006)
  • Author(s): Yamada, J. et al.
  • Journal Title: Biochem.Biophys.Res.Commun. 349・3 Pages: 913-919
• [Journal Article] Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E_2 production of microglia. (2006)
  • Author(s): Zhang, J. et al.
  • Journal Title: J.Neuroimmunol. 172・1-2 Pages: 112-120
• [Journal Article] Potentiation of the NMDA receptor-mediated responses through the activation of the glycine site by microglial secreting soluble factor. (2006)
  • Author(s): Hayashi, Y. et al.
  • Journal Title: Glia 53・6 Pages: 660-668
• [Journal Article] Amyloid-β fibril formation is not necessazily required for microglial activation by the peptides. (2005)
  • Author(s): Hashioka S, et. al.
  • Journal Title: Neurochemistry International 47 Pages: 369-376
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice (2005)
  • Author(s): Shimizu T, et. al.
  • Journal Title: Journal of Neurochemistry 94 Pages: 680-690
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Leptomeningeal cells activate microglial and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation (2005)
  • Author(s): Wu Z, et. al.
  • Journal Title: Journal of Neuroimmunology 167 Pages: 90-98
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Proteases and synaptic activity.In:Proteases (2005)
  • Author(s): Nakanishi H.(分担)
  • Journal Title: Biology and Disease.Vol.3, (Eds:Lendeckel, U.and Hooper, N.), Kluwer Academic/Plenum Publishers
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Amyloid-β fibril formation is not necessarily required for microglial activation by the peptides (2005)
  • Author(s): Hashioka, S., Monji, A., Ueda, T., Kanba, S., Nakanishi, H
  • Journal Title: Neurochem. Int 47 Pages: 369-376
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice (2005)
  • Author(s): Shimizu, T., Hayashi, Y., Yamasaki, R., Yamada, J., Zhang, J., Ukai, K., Koike, M., Mine, K., von Figura, K., Peters, C., Saftig, P., Fukuda, T., Uchiyama, Y., Nakanishi, H
  • Journal Title: J. Neurochem 94 Pages: 680-690
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Leptomeningeal cells activate microglial and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation (2005)
  • Author(s): Wu, Z., Zhang, J., Nakanishi, H
  • Journal Title: J. Neuroimmunol 167 Pages: 90-98
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Amyloid-β fibril formation is not necessarily required for microglial activation by the peptides (2005)
  • Author(s): Hashioka, S. et al.
  • Journal Title: Neurochem.Int. 47・5 Pages: 369-376
• [Journal Article] Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice. (2005)
  • Author(s): Shimizu, T. et al.
  • Journal Title: J.Neurochem.et al. 94・3 Pages: 680-690
• [Journal Article] Leptomeningeal cells activate microglial and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation. (2005)
  • Author(s): Wu, Z.et al.
  • Journal Title: J.Neuroimmunol. 167・1-2 Pages: 90-98
• [Presentation] Synaptic Strippingにおける細胞外ヌクレオチドの関与 (2008)
  • Author(s): 中西 博
  • Organizer: 第81回日本薬理学会総会、シンポジウム:細胞外ヌクレオチドによる脳機能制御-分子ダイナミクスと疾病への関与
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Synaptic Stripping における細胞外ヌクレオチドの関与 (2008)
  • Author(s): 中西 博
  • Organizer: 第81回日本薬理学会総会、シンポジウム:細胞外ヌクレオチドによる脳機能制御-分子ダイナミクスと疾病への関与
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-17
• [Presentation] Modulation of NMDA receptor-mediated responses by microglial secreting soluble factors (2007)
  • Author(s): Hayashi Y.and Nakanishi H.
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ
  • Year and Date: 2007-11-07
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Modulation of NMDA receptor-mediated responses bymicroglial secreting soluble factors (2007)
  • Author(s): Hayashi, Y., Nakanishi, H
  • Organizer: 37 th Society for Neuroscience Meeting
  • Year and Date: 2007-11-07
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Modulation of NMDA receptor-mediated responses by microglial secreting soluble factors. (2007)
  • Author(s): Hayashi Y.and Nakanishi H.
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ
  • Year and Date: 2007-11-07
• [Presentation] Induction of age-related differential cytokine responses in the brain through microglia by systemic inflammation (2007)
  • Author(s): Wu Z.and Nakanishi H.
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ
  • Year and Date: 2007-11-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Overproduction of nitric oxide by microglia due to lysosomal storage-induced p38 MAP kinase activation in cathepsin D-deficient mice (2007)
  • Author(s): Nakanishi H., Wu Z., and Ochi-Shindou M
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ
  • Year and Date: 2007-11-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Induction of age-related differential cytokine responses in the brain through microglia by systemic inflammation (2007)
  • Author(s): Wu, Z., Nakanishi, H
  • Organizer: 37 th Society for Neuroscience Meeting
  • Year and Date: 2007-11-06
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Overproduction of nitric oxide by microglia due to lysosomal storage-induced p38 MAP kinase activation in cathepsin D-deficient mice (2007)
  • Author(s): Nakanishi, H., Wu, H., Ochi-Shindou, M
  • Organizer: 37th Society for Neuroscience Meeting
  • Year and Date: 2007-11-06
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Systemic inflammation induces age-dependent defferential activation of glial cells through the leptomeninges (2007)
  • Author(s): Wu Z.and Nakanishi H.
  • Organizer: 第8回ヨーロッパグリア(Euroglia)会議
  • Place of Presentation: ロンドン
  • Year and Date: 2007-09-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Systemic inflammation induces age- dependent defferential activation of glial cells through the leptomeninges (2007)
  • Author(s): Wu, Z., Nakanishi, H
  • Organizer: 18th Euroglia Meeting
  • Year and Date: 2007-09-06
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Systemic inflammation induces age-dependent defferential activation of glial cells through the leptomeninges. (2007)
  • Author(s): Wu Z.and Nakanishi H.
  • Organizer: 第8回ヨーロッパグリア(Euroglia)会議
  • Place of Presentation: ロンドン
  • Year and Date: 2007-09-06
• [Presentation] The intra-arterial injection of microgliaprotects hippocampal CA1 neuronsagainst global ischemia-induced functional deficits in rats (2006)
  • Author(s): Hayashi Y, et. al.
  • Organizer: 第36回北米神経科学会
  • Place of Presentation: アトランタ
  • Year and Date: 2006-10-15
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The intra- arterial injection of microglia protects hippocampal CA1 neurons against global ischemia-induced functional deficits in rats (2006)
  • Author(s): Hayashi, Y., Suzuki, H., Sawada, M., Nakanishi, H
  • Organizer: 36th Society for Neuroscience Meeting
  • Place of Presentation: Atlanta
  • Year and Date: 2006-10-05
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] ミクログリアによる神経保護機構:闇と光のスイッチング機構 (2006)
  • Author(s): 中西 博
  • Organizer: 第18回日本神経免疫学会、シンポジウム「免疫学的機序による神経細胞傷害」
  • Place of Presentation: 名古屋
  • Year and Date: 2006-03-02
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Deficiency of lysosomal proteases and disorderdes neuronal and microglial functions (2005)
  • Author(s): 中西 博
  • Organizer: 第48回日本神経化学会、理事会企画公開シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2005-09-29
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] ミクログリアのマクロファージ様機能と脳特異的機能 (2005)
  • Author(s): 中西 博
  • Organizer: 第17回日本神経免疫学会、モーニングセミナー
  • Place of Presentation: 福岡
  • Year and Date: 2005-03-03
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Age-dependent differential activation profiles of glial cells by the leptomeninges during systemic inflammation:In Neuroimmunology Research Focus, (Broglio PV ed) (2007)
  • Author(s): Wu Z. and Nakanish i H.(分担)
  • Publisher: Nova Science Publishers Inc.
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Microglial Proteases:In Neural Protein Metabolism & Function.Handbook of Neurochemistry and Molecular Neurobiology, Vol.7(Lajtha A ed) (2007)
  • Author(s): Nakanishi H.(分担)
  • Publisher: Kluwer Publishing Corporation
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Age-dependent differential activation profiles of glial cells by the leptomeninges during systemic inflammation:In Neuroimmunology Research Focus, (Broglio PV ed) (2007)
  • Author(s): Wu Z.and Nakanishi H.(分担)
  • Publisher: Nova Science Publishers Inc.
• [Book] Microglial Proteases:In Neural Protein Metabolism and Function.Handbook of Neurochemistry and Molecular Neurobiology, Vol.7(Lajtha A ed) (2007)
  • Author(s): Nakanishi H.(分担)
  • Publisher: Kluwer Publishing Corporation
• [Book] Kluwer Academic/Plenum Publishers (2005)
  • Author(s): Nakanishi H.(分担)
  • Publisher: Proteases and synaptic activity.In:Proteases in Biology and Disease.Vol.3, (Eds:Lendeckel, U.and Hooper, N.)
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Proteases in the Brain(Proteases and synaptic activity) (2005)
  • Author(s): Nakanishi, H.
  • Publisher: Kluwer Academic/Plenum Publisher