The mechanisms of anti-Alzheimer dicaam effects by NSAIDs

• Project/Area Number: 18591287
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: TAKASHI Morihara Osaka University, Graduate School of Medicine, Assistant Professor (90403196)
• Co-Investigator(Kenkyū-buntansha): KUDO Takashi Osaka Univetsty, Graduate School of Medicine, Associate Professor (10273632) ; TANAKA Toshihisa Osaka Univetsty, Graduate School of Medicine, Associate Professor (10294068) ; OKOCHI Masayasu Osaka Univetsty, Graduate School of Medicine, Assistant Professor (90335357) ; TAGAMI Shinji Osaka Univetsty, Graduate School of Medicine, Assistant Professor (40362735) ; TAKEDA Masatashi Osaka Univetsty, Takeda Graduate School of Medicine, Professor (00179649)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,520,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥420,000); Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: Alzheimer disease / Inflammation / NSAID / micro glia / Treatment / NSAID / アミロイドβ

Research Abstract

Background Inflammation is one pathological change in Alzheimer (AD) brain and closely related to activation of microglia which can clear amyloid beta protein (Ab) and/or muse neurodegeneration. Our group demonstrated that NSAID (ibuprofen) suppresses amyloid pathology in Alzheimer model mice, that is confirmed by more than 11 in vivo studies. We previously showed that ibuprofen suppressed levels of IL-lb and al-antichymohypsin. On the other hand, amyloid pathology in APP Tg mice is also reduced by Ab vaccination. Vaccination which caused brain inflammation in a clinical trial is pro-infammatory and activates microglia, one potential anti- AD mechanism of vaccination. Both NSAID and Ab vaccination suppress amyloid pathology but have contrasting effects on inflammation. This possible conflict between NSAID and Ab vaccine was addressed in this study.
Results Ibuprofen levels in APP Tg mice (TG2576) fed with 375ppm ibuprofen in diet, which has been shown to suppress amyloid burden (-55.9%) were measured. Ibuprofen levels in plasma, liver and brain were 47.04+5.17uM which was dose to the therapeutic window of rheumatoid patients, 14361-L80uM and 4.07+2.03uM which is above the COX inhibition IC50 in whole blood assays. These results suggested that ibuprofen in this dose have anti-infammatory effects. Multiple microglial markers were evaluated. CD11b and CD11c immunoreactivity per amyloid plaque in APP Tg mice were not suppressed by ibuprofen. Though amyloid burden which can stimulate microglia was suppressed, global mRNA levels of CD11b, CD11c, CD68 (macrosialin) nor iNOS in cortex were not suppressed by ibuprofen. In primary cultured microglia cells, 5-50uM ibuprofen inhibited COX activity, but did not suppress mRNA levels of CD11b, CD11c and CD68. At extremely high level of ibuprofen (500uM) suppressed the expression levels of CD11c and CD11b mRNA. These data suggested that middle or high dose of ibuprofen suppress inflammation without disturbance of microglia activation.
Conclusion In vivo and in vitro data suggested that 375ppm in diet ibuprofen suppresses amyloid pathology but does not disturb microglia activation which can clear Ab. There is no evidence to show a real conflict between ibuprofen and Ab vaccine.

Research Products

• [Journal Article] Omega-3 Fatty Acid Docosahexaenoic Acid Increases Sorla/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer Disease(AD): Relevance to AD Prevention (2007)
  • Author(s): Q.-L. MA, B. TETER, 丁. MORIHARA, O. J. UBEDA, F. YANG, W. BEECH, G. P. LIM, S. FRAUTSCHY, G. M. COLE
  • Journal Title: J Neurosci 27(52) Pages: 14299-307
  • Description: 「研究成果報告書概要(和文)」より
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• [Journal Article] Peripheral ethanolamine plasmalogen deficiency: A logical causative factor in Alzheimer's disease and dementia. (2007)
  • Author(s): Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, WK Ahiahonu P, Heath D, Yamazaki Y, Flax J, Krenitsky KF, Sparks DL, Lerner A, Friedland RP, Kudo T, Kamino K, _Morihara T, Takeda M, Wood PL.
  • Journal Title: J Lipid Res. 48(11) Pages: 2485-98
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Omega-3 Fatty Acid Docosahexaenoic Acid Increases Soria/ LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer Disease (AD) : Relevance to AD Prevention (2007)
  • Author(s): Q.-L., MA, B., TETER, T., MORIHARA, O.J., UBEDA, F., YANG, W., BEECH, G.P., LIM, S., FRAUTSCHY, G.M., COLE
  • Journal Title: JNeurosci 27(52) Pages: 14299-307
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Peripheral ethanolamine plasmalogen deficiency : A logical causative factor in Alzheimer's disease and dementia (2007)
  • Author(s): Goodenowe, DB, Cook, LL, Liu, J, Lu, Y, Jayasinghe, DA, WK, Ahiahonu P, Heath D, Yamazaki Y, Flax, J, Krenitsky, KF, Sparks, DL, Lerner, A, Friedland, RP, Kudo, T, Kamino, K, Morihara, T, Takeda, M, Wood, PL
  • Journal Title: J Lipid Res 48(11) Pages: 2485-98
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Omega-3 Fatty Acid Docosahexaenoic Acid Increases Sorla/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer Disease(AD): Relevance to AD Prevention (2007)
  • Author(s): Q. -L. MA. B. TETER, T. MORIHARA, O. J. UBEDA, F. YANG, W. BEECH, G. P. LIM, S. FRAUTSCHY, G. M. COLE
  • Journal Title: J Neurosci 27 Pages: 14299-14307
  • Peer Reviewed
• [Journal Article] Peripheral ethanolamine plasmalogen deficiency: A logical causative factor in Alzheimer's disease and dementia. (2007)
  • Author(s): Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, W K Ahiahonu P, Heath D, Yamazaki Y, Flax J, Krenitsky KF, Sparks DL, Lerner A, Friedland RP, Kudo T, Kamino K, Morihara T, Takeda M, Wood PL.
  • Journal Title: J Lipid Res. 48 Pages: 2485-2498
  • Peer Reviewed
• [Journal Article] Multiple anti-Alzheimer disease activities of non-steroidal anti-inflammatory drugs. (2006)
  • Author(s): Morihara T, Cole GM, Tanii H, Tanaka T, Kudo T, Takeda M
  • Journal Title: Psychogeriatrics 6(1)
  • NAID: 10019375931
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• [Journal Article] Toll-like receptor 3 mediated hyperphosphorylation of tau in human SH-SY5Y neuroblastoma cells. (2006)
  • Author(s): Nessa BN, Tanaka T, Kamino K, Sadik G, Ansar AB, Kimura R, Tanii H, Okochi M, Morihara T, Tagami S, Kudo T, Takeda M.
  • Journal Title: Psychiatry Clin Neurosci 60 Suppl
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• [Journal Article] Presenilin-dependent gamma-secretase on plasma membrane and endosomes is functionally distinct. (2006)
  • Author(s): Fukumori A, Okochi M, Tagami S, Jiang J, Itoh N, Nakayama T, Yanagida K, Ishizuka-Katsura Y, Morihara T, Kamino K, Tanaka T, Kudo T, Tanii H, Ikuta A, Haass C, Takeda M.
  • Journal Title: Biochemistry. 45(15)
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• [Journal Article] Altered localization of amyloid precursor protein under endoplasmic reticulum stress. (2006)
  • Author(s): Kudo T, Okumura M, Imaizumi K, Araki W, Morihara T, Tanimukai H, Kamagata E, Tabuchi N, Kimura R, Kanayama D, Fukumori A, Tagami S, Okochi M, Kubo M, Tanii H, Tohyama M, Tabira T, Takeda M.
  • Journal Title: Biochem Biophys Res Commun. 344(2)
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• [Journal Article] Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease (2006)
  • Author(s): Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Frautschy SA, Cole GM.
  • Journal Title: Nat Neurosci. 9(2)
  • Description: 「研究成果報告書概要(和文)」より
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• [Journal Article] Multiple anti-Alzheimer disease activities of non-steroidal anti-inflammatory drugs (2006)
  • Author(s): Morihara, T, Cole, GM, Tanii, H, Tanaka, T, Kudo, T, Takeda, M
  • Journal Title: Psychogeriatrics 6(1) Pages: 1-3
  • NAID: 10019375931
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Toll-like receptor 3 mediated hyperphosphorylation of tau in human SH-SY5Y neuroblastoma cells (2006)
  • Author(s): Nessa, BN, Tanaka, T, Kamino, K, Sadik, G, Ansar, AB, Kimura, R, Tanii, H, Okochi, M, Morihara, T, Tagami, S, Kudo, T, Takeda, M
  • Journal Title: Psychiatry Clin Neurosci 60,1 Pages: 527-33
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Presenilin-dependent gamma-secretase on plasma membrane and endosomes is functionally distinct (2006)
  • Author(s): Fukumori, A, Okochi, M, Tagami, S, Jiang, J, Itoh, N, Nakayama, T, Yanagida, K, Ishizuka-Katsura Y, Morihara, T, Kamino, K, Tanaka, T, Kudo, T, Tanii, H, Ikuta, A, Haass, C, Takeda, M
  • Journal Title: Biochemistry 45(15) Pages: 4907-14
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• [Journal Article] Altered localization of amyloid precursor protein under endoplasmicreticulum stress (2006)
  • Author(s): Kudo, T, Okumura, M, Imaizumi, K, Araki, W, Morihara, T, Tanimukai, H, Kamagata, E, Tabuchi, N, Kimura, R, Kanayama, D, Fukumori, A, Tagami, S, Okochi, M, Kubo, M, Tanii, H, Tohyama, MTabira, T, Takeda, M
  • Journal Title: Biochem BiophysReCommun 344(2) Pages: 525-30
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• [Journal Article] Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease (2006)
  • Author(s): Zhao, L, Ma, QL, Calon, F, Harris-White, ME, Yang, F, Lim, GP, Morihara, T, Ubeda, OJ, Ambegaokar, S, Hansen, JE, Weisbart, RH, Teter, B, Frautschy, SA, Cole, GM
  • Journal Title: Nat Neurosci 9(2) Pages: 234-42
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• [Journal Article] Multiple anti-Alzheimer disease activities of non-steroidal anti-inflammatory drugs. (2006)
  • Author(s): Morihara T, Cole GM, Tanii H, Tanaka T, Kudo T, Takeda M
  • Journal Title: Psychogeriatrics 6 (1) Pages: 1-3
  • NAID: 10019375931
• [Journal Article] Toll-like receptor 3 mediated hyperphosphorylation of tau in human SH-SY5Y neuroblastoma cells. (2006)
  • Author(s): Nessa BN, Tanaka T, Kamino K, Sadik G, Ansar AB, Kimura R, Tanii H, Okochi M, Morihara T, Tagami S, Kudo T, Takeda M
  • Journal Title: Psychiatry Clin Neurosci. 60 Suppl 1
• [Journal Article] Presenilin-dependent gamma-secretase on plasma membrane and endosomes is functionally distinct. (2006)
  • Author(s): Fukumori A, Okochi M, Tagami S, Jiang J, Itoh N, Nakayama T, Yanagida K, Ishizuka-Katsura Y, Morihara T, Kamino K, Tanaka T, Kudo T, Tanii H, Ikuta A, Haass C, Takeda M
  • Journal Title: Biochemistry 45 (15) Pages: 4907-4914
• [Journal Article] Altered localization of amyloid precursor protein under endoplasmic reticulum stress. (2006)
  • Author(s): Kudo T, Okumura M, Imaizumi K, Araki W, Morihara T, Tanimukai H, Kamagata E, Tabuchi N, Kimura R, Kanayama D, Fukumori A, Tagami S, Okochi M, Kubo M, Tanii H, Tohyama M, Tabira T, Takeda M.
  • Journal Title: Biochem Biophys Res Commun 344(2) Pages: 525-530
• [Journal Article] Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease (2006)
  • Author(s): Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Frautschy SA, Cole GM.
  • Journal Title: Nat Neurosci. 9 (2) Pages: 234-242
• [Presentation] "Anti-Alzheimer drug NSAID has no trade-off effects among anti-inflammation, microglial activation and suppression of amyloid pathology" (2007)
  • Author(s): T Morihara, Y Mori, M. Takeda, S. Boudinot, F. D. Boudinot, F. Yang, S. A. Frautschy, G. M. Cole,
  • Organizer: Society for Neuroscience 2007
  • Place of Presentation: San Diego
  • Year and Date: 2007-11-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Anti-Alzheimer drug NSAID has no trade-off effects among anti-inflammation, microglial activation and suppression of amyloid pathology (2007)
  • Author(s): T, Morihara, Y, Mori, M., Takeda, S., Boudinot, F.D., Boudinot, F., Yang, S.A., Frautschy, G.M., Cole
  • Organizer: Society for Neuroscience 2007
  • Place of Presentation: San Diego
  • Year and Date: 2007-11-06
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Anti-Alzheimer drug NSAID has no trade-off effects among anti-inflammation, microglial activation and suppression of amyloid pathology (2007)
  • Author(s): T Morihara, Y. Mori, M. Takeda, S. Boudinot, F.D. Boudinot, F. Yang, S.A. Frautschy, G.M. Cole
  • Organizer: Society for Neuroscience
  • Place of Presentation: San Diego
  • Year and Date: 2007-11-06
• [Presentation] Anti-Alzheimer drug NSAID has NO trade-off effects among anti-inflammation, microglial activation and suppression of amyloid pathology (2007)
  • Author(s): T Morihara, Y Mori, M. Takeda, S. Boudinot, F.D. Boudinot, F. Yang, S.A. Frautschy, G.M. Cole
  • Organizer: 国際老年精神学会IPA
  • Place of Presentation: 大阪
  • Year and Date: 2007-10-18
• [Presentation] "Design report: Randomized prospective learning therapy study on elderly Japanese in Osaka" (2007)
  • Author(s): Takashi morihara, Hiroaki Kazui, Ayumi kono, Takahiro Higashi, Masuhiro okuda, Yaeko hata, Hiromi yoshida, Kousuke masuda, Masatoshi Takeda
  • Organizer: IPA2007
  • Place of Presentation: Osaka
  • Year and Date: 2007-10-16
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] "Anti-Alzheimer drug NSAID has NO trade-off effects among anti-inflammation, microglial activation and suppression of amyloid pathology" (2007)
  • Author(s): T Morihara, Y Mori, M. Takeda, S. Boudinot, F. D. Boudinot, F. Yang, S. A. Frautschy, G. M. Cole
  • Organizer: IPA2007
  • Place of Presentation: Osaka
  • Year and Date: 2007-10-16
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Design report : Randomized prospective learning therapy study on elderly Japanese in Osaka (2007)
  • Author(s): Takashi, morihara, Hiroaki, Kazui, Ayumi, kono, Takahiro, Higashi, Masuhiro, okuda, Yaeko, hata, Hiromi, yoshida, Kousuke, masuda, Masatoshi, Takeda
  • Organizer: IPA 2007
  • Place of Presentation: Osaka
  • Year and Date: 2007-10-16
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Anti-Alzheimer drug NSAID has NO trade-off effects among anti-inflammation, microglial activation and suppression of amyloid pathology (2007)
  • Author(s): T, Morihara, Y, Mori, M., Takeda, S., Boudinot, F.D., Boudinot, F., Yang, S.A., Frautschy, G.M., Cole
  • Organizer: IPA 2007
  • Place of Presentation: Osaka
  • Description: 「研究成果報告書概要(欧文)」より