Research on the mechanism underlying the accelerated senescence in cathepsin D-deficient mice
| Project/Area Number |
17390495
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Kyushu University |
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Principal Investigator |
NAKANISHI Hiroshi Kyushu University, Faculty of Dental Sciences, Professor (20155774)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥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)
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| 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.
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Report
(4 results)
Research Products
(63 results)
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[Journal Article] Phospholipids modulate superoxide and nitric oxide production by lipopolysaccharide and phorbol 12-myristate-13-acetate-activated microglia2007
Author(s)
Hashioka, S., Han, Y-H., Fujii, S., Kato, H., Monji, A., Utsumi, H., Sawada, M., Nakanishi. H., Kanba, S
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Journal Title
Neurochem. Int 50
Pages: 499-506
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Phosphatidylserine and phosphatidylcholine-containing liposomes inhibit amyloid β and interferon-γ-induced microglial activation2007
Author(s)
Hashioka, S., Han, Y-H., Fujii, S., Kato, H., Monji, A., Utsumi, H., Sawada, M., Nakanishi H., Kanba, S
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Journal Title
Free Rad. Biol. Med 42
Pages: 945-954
Description
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[Journal Article] Involvement of lysosomal storage- induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice2007
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
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Journal Title
Mol. Cell. Neurosci 35
Pages: 573-584
Description
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[Journal Article] Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E_2 production of microglia2006
Author(s)
Zhang, J., Fujii, S., Hashioka, S., Tanaka, Y., Wu, Z., Shiratsuchi, A., Nakanishi, Y., Nakanishi, H
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Journal Title
J. Neuroimmunol 172
Pages: 112-120
Description
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[Journal Article] The intra-arterial injection of microglia protects hippocampal CA1 neurons against global ischemia-induced functional deficits in rats2006
Author(s)
Hayashi, Y., Tomimatsu, Y., Suzuki, H., Yamada, J., Yao, H., Kagamiishi, Y., Tateishi, N., Sawada, M., Nakanishi, H
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Journal Title
Neuroscience 142
Pages: 87-96
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[Journal Article] Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice2005
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
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Journal Title
J. Neurochem 94
Pages: 680-690
Description
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[Book] Kluwer Academic/Plenum Publishers2005
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
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