アルツハイマー病治療の開発：食物由来のβーアミロイド蛋白抑制物質と環境療法の探索

• 研究課題/領域番号: 22500320
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 神経解剖学・神経病理学
• 研究機関: 埼玉医科大学
• 研究代表者: 森 隆 埼玉医科大学, 医学部, 准教授 (60239605)
• 研究分担者: 山口 晴保 群馬大学, 医学部, 教授 (00158114)
• 研究期間 (年度): 2010-04-01 – 2014-03-31
• 研究課題ステータス: 完了 (2013年度)
• 配分額: 4,290千円 (直接経費: 3,300千円、間接経費: 990千円); 2013年度: 780千円 (直接経費: 600千円、間接経費: 180千円); 2012年度: 1,040千円 (直接経費: 800千円、間接経費: 240千円); 2011年度: 1,170千円 (直接経費: 900千円、間接経費: 270千円); 2010年度: 1,300千円 (直接経費: 1,000千円、間接経費: 300千円)
• キーワード: アルツハイマー病 / アミロイドβ蛋白 / 神経病理学 / フェノール化合物 / 遺伝子改変マウス / 神経科学 / 神経変性疾患 / ポリフェノール / 細胞・組織 / 獣医学

研究概要

アルツハイマー病（AD）の臨床試験では、designer drugによる副作用・症状の悪化が問題視されている。我々は、secretaseに作用する多様な活性を持った植物/食物由来のnutraceuticalsに着目した。Tannic acid（TA）/ferulic acid（FA）の様なフェノール化合物を、脳血管アミロイド症の遺伝子改変PSAPPマウスモデルに経口投与し、認知機能とAD様の病態を評価した。TA/FAの投与は、1）行動学的障害、2）脳アミロイド症、3）脳炎症反応を抑制・遅延させた。さらに、これらの化合物がβ-secretaseの蛋白発現と活性を抑制することが明らかになった。

研究成果

• [雑誌論文] Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice (2014)
  • 著者名/発表者名: Johnathon Alex Grizzell, Alexandre Iarkov, Rosalee Holmes, Takashi Mori, Valentina Echeverria
  • 雑誌名: Behav Brain Res 巻: (in press) ページ: 55-65
  • DOI: 10.1016/j.bbr.2014.03.047
  • 査読あり
• [雑誌論文] Mycoplasma hyorhinis markedly degradesβ-amyloid peptides in vitro and ex vivo : a novel biological approach for treating Alzheimer's disease? (2013)
  • 著者名/発表者名: Ahsan Habib, Juan Deng, Huayan Hou, Qiang Zou, Brian Giunta, Yan-Jiang Wang, Demian Obregon, Darrell Sawmiller, Song Li, Takashi Mori, Jun Tan
  • 雑誌名: Am J Transl Res 巻: 5 (6) ページ: 634-642
  • 査読あり
• [雑誌論文] Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation (2013)
  • 著者名/発表者名: She-Qing Zhang, Darrell Sawmiller, Song Li, Kavon Rezai-Zadeh, Huayan Hou, Shufeng Zhou, Douglas Shytle, Brian Giunta, Frank Fernandez, Takashi Mori, Jun Tan
  • 雑誌名: PLoS ONE 巻: 8 (8) 号: 8 ページ: e71913-e71913
  • DOI: 10.1371/journal.pone.0071913
  • 査読あり
• [雑誌論文] Ferulic acid is a nutraceuticalβ-secretase modulator that improves behavioral impairment and Alzheimer-like pathology in transgenic mice (2013)
  • 著者名/発表者名: Takashi Mori, Naoki Koyama, Marie-Victoire Guillot-Sestier, Jun Tan, Terrence Town
  • 雑誌名: PLoS ONE 巻: 8 (2) 号: 2 ページ: e55774-e55774
  • DOI: 10.1371/journal.pone.0055774
  • 査読あり
• [雑誌論文] Mycoplasma hyorhinis markedly degrades β-amyloid peptides in vitro and ex vivo: a novel biological approach for treating Alzheimer’s disease? (2013)
  • 著者名/発表者名: Ahsan Habib, Juan Deng, Huayan Hou, Qiang Zou, Brian Giunta, Yan-Jiang Wang, Demian Obregon, Darrell Sawmiller, Song Li, Takashi Mori, Jun Tan
  • 雑誌名: Am J Transl Res 巻: 5 (6) ページ: 634-642
  • 査読あり
• [雑誌論文] Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce Aβ-associated neuropathology in Alzheimer mice. (2013)
  • 著者名/発表者名: Donna Darlington
  • 雑誌名: Stem Cells Dev 巻: 22(3) 号: 3 ページ: 412-421
  • DOI: 10.1089/scd.2012.0345
  • 査読あり
• [雑誌論文] sAPP-αmodulatesβ-secretase activity and amyloid-βgeneration (2012)
  • 著者名/発表者名: Demian Obregon, Huayan Hou, Juan Deng, Brian Giunta, Jun Tian, Donna Darlington, MD Shahaduzzaman, Yuyuan Zhu, Takashi Mori, Mark P. Mattson, Jun Tan
  • 雑誌名: Nat Commun 巻: 3 号: 1 ページ: 777-777
  • DOI: 10.1038/ncomms1781
  • 査読あり
• [雑誌論文] Tannic acid is a naturalβ-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice (2012)
  • 著者名/発表者名: Takashi Mori, Kavon Rezai-Zadeh, Naoki Koyama, Gary W. Arendash, Haruyasu Yamaguchi, Nobuto Kakuda, Yuko Horikoshi-Sakuraba, Jun Tan, Terrence Town
  • 雑誌名: J Biol Chem 巻: 287 (9) 号: 9 ページ: 6912-6927
  • DOI: 10.1074/jbc.m111.294025
  • 査読あり
• [雑誌論文] Autoreactive-Aβantibodies promote APPβ-secretase processing (2012)
  • 著者名/発表者名: Juan Deng, Huayan Hou, Brian Giunta, Takashi Mori, Yan-Jiang Wang, Frank Fernandez, Sascha Weggen, Wataru Araki, Demian Obregon, Jun Tan
  • 雑誌名: J Neurochem 巻: 120 (5) 号: 5 ページ: 732-740
  • DOI: 10.1111/j.1471-4159.2011.07629.x
  • 査読あり
• [雑誌論文] Long-term electromagnetic field treatment increases brain neuronal activity: Linkage to cognitive benefit and therapeutic implications for Alzheimer’s disease. (2012)
  • 著者名/発表者名: Takashi Mori
  • 雑誌名: J Alzheimer's Dis Park 巻: 1 号: 02 ページ: 102-102
  • DOI: 10.4172/2161-0460.1000102
  • 査読あり
• [雑誌論文] Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit. (2012)
  • 著者名/発表者名: Gary W. Arendash
  • 雑誌名: PLoS ONE 巻: 7(4) 号: 4 ページ: e35751-e35751
  • DOI: 10.1371/journal.pone.0035751
  • 査読あり
• [雑誌論文] Tannic acid is a natural β-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice (2012)
  • 著者名/発表者名: Takashi Mori, et al
  • 雑誌名: J Biol Chem 巻: 287 ページ: 6912-6927
  • 査読あり
• [雑誌論文] Cotinine reduces amyloid-βaggregation and improves memory in Alzheimer's mice (2011)
  • 著者名/発表者名: Valentina Echeverria, Ross Zeitlin, Sarah Burgess, Sagar Patel, Arghya Barman, Garima Thakur, Magorzota B. Mamcarz, Li Wang, David B. Sattelle, Daniel A Kirschner, Takashi Mori, Roger M. Leblanc, Rajeev Prabhakar, Gary W. Arendash
  • 雑誌名: J Alzheimer's Dis 巻: 24 (4) 号: 4 ページ: 817-835
  • DOI: 10.3233/jad-2011-102136
  • 査読あり
• [雑誌論文] CD45 deficiency drives Aβoligomers and neuronal loss in Alzheimer's disease mice (2011)
  • 著者名/発表者名: Yuyan Zhu, Huayan Hou, Brian Giunta, Amanda Ruscin, Carmelina Gemma, JingJi Jin, Natasa Dragicevic, Patrick Bradshaw, Suhail Rasool, Charles Glabe, Paula Bickford, Takashi Mori, Demian F. Obregon, Terrence Town, Jun Tan
  • 雑誌名: J Neurosci 巻: 31 (4) 号: 4 ページ: 1355-1365
  • DOI: 10.1523/jneurosci.3268-10.2011
  • 査読あり
• [雑誌論文] Granulocyte-colony stimulating factor (G-CSF) enhances recovery in mouse model of Parkinson's disease (2011)
  • 著者名/発表者名: Shijie Song, Vasyl Sava, Amanda Rowe, Kunyu Lia, Chuanhai Cao, Takashi Mori, Juan Sanchez-Ramos
  • 雑誌名: Neurosci Lett 巻: 487 (2) 号: 2 ページ: 153-157
  • DOI: 10.1016/j.neulet.2010.10.012
  • 査読あり
• [雑誌論文] Mutant presenilin-1 deregulated peripheral immunity exacerbates Alzheimer-like pathology (2011)
  • 著者名/発表者名: Yuyan Zhu, Demian F. Obregon, Huayan Hou, Brian Giunta, Jared Erhart, Frank Fernandez, Takashi Mori, William Nikolic, Yangbing Zhao, Dave Morgan, Terrence Town, Jun Tan
  • 雑誌名: J Cell Mol Med 巻: 15 (2) 号: 2 ページ: 327-338
  • DOI: 10.1111/j.1582-4934.2009.00962.x
  • 査読あり
• [雑誌論文] Targeting S100B in cerebral ischemia and in Alzheimer's disease (2010)
  • 著者名/発表者名: Takashi Mori, Takao Asano, Terrence Town
  • 雑誌名: Cardiovasc Psychiatry Neurol 巻: Vol. 2010
  • 査読あり
• [雑誌論文] GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice (2010)
  • 著者名/発表者名: Timothy D. Boyd, Steven P. Bennett, Takashi Mori, Nickolas Governatori, Melissa J. Runfeldt, Michelle Norden, Jaya Padmanabhan, Peter Neame, Inge Wefes, Juan Sanchez-Ramos, Gary W. Arendash, Huntington Potter
  • 雑誌名: J Alzheimer's Dis 巻: 21 (2) 号: 2 ページ: 507-518
  • DOI: 10.3233/jad-2010-091471
  • 査読あり
• [雑誌論文] Rapamycin promotesβ-amyloid production via ADAM-10 inhibition (2010)
  • 著者名/発表者名: Shequing Zhang, Jon Salemi, Huayan Hou, Yuyan Zhu, Takashi Mori, Brian Giunta, Demian F. Obregon, Jun Tan
  • 雑誌名: Biochem Biophys Res Commun 巻: 398 (3) 号: 3 ページ: 337-341
  • DOI: 10.1016/j.bbrc.2010.06.017
  • 査読あり
• [雑誌論文] Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease. (2010)
  • 著者名/発表者名: Takashi Mori
  • 雑誌名: Glia 巻: 58 ページ: 300-314
  • 査読あり
• [雑誌論文] Rapamycin promotes β-amyloid production via ADAM-10 inhibition. (2010)
  • 著者名/発表者名: Shequing Zhang
  • 雑誌名: Biochem Biophys Res Commun 巻: 398 ページ: 337-341
  • 査読あり
• [雑誌論文] GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. (2010)
  • 著者名/発表者名: Timothy D.Boyd
  • 雑誌名: J Alzheimer's Dis 巻: 21 ページ: 507-518
  • 査読あり
• [学会発表] Octyl gallate promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation (2013)
  • 著者名/発表者名: Darrell Sawmiller, She-Qing Zhang, Kavon Rezai-Zadeh, Huayan Hou, Jared Ehrhart, Douglas Shytle, Shufeng Zhou, Brian Giunta, Takashi Mori, Jun Tan
  • 学会等名: Neuroscience 13
  • 発表場所: San Diego, U.S.A
  • 年月日: 2013-11-12
• [学会発表] Methylene blue reverses behavioral impairment and ameliorates cerebral amyloidosis in PSAPP mice (2013)
  • 著者名/発表者名: Takashi Mori, Naoki Koyama, Tatsuya Segawa, Noriaki Kinoshita, Huayan Hou, Jun Tan, Terrence Town
  • 学会等名: Neuroscience 13
  • 発表場所: San Diego, U.S.A
  • 年月日: 2013-11-12
• [学会発表] Soluble amyloid precursor protein-αmodulatesβ-secretase activity and amyloid-βgeneration (2013)
  • 著者名/発表者名: Demian Obregon, Huayan Hou, Juan Deng, Brian Giunta, Jun Tian, Donna Darlington, Md Shahaduzzaman, Takashi Mori, Mark P. Mattson, Jun Tan
  • 学会等名: Neuroscience 13
  • 発表場所: San Diego, U.S.A
  • 年月日: 2013-11-09
• [学会発表] Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation. (2013)
  • 著者名/発表者名: Demian Obregon, Huayan Hou, Juan Deng, Brian Giunta, Jun Tian, Donna Darlington, Md Shahaduzzaman, Takashi Mori, Mark P. Mattson, Jun Tan
  • 学会等名: Neuroscience 13
  • 発表場所: San Diego, U.S.A.
• [学会発表] Methylene blue reverses behavioral impairment and ameliorates cerebral amyloidosis in PSAPP mice. (2013)
  • 著者名/発表者名: Takashi Mori, Naoki Koyama, Tatsuya Segawa, Noriaki Kinoshita, Huayan Hou, Jun Tan, Terrence Town
  • 学会等名: Neuroscience 13
  • 発表場所: San Diego, U.S.A.
• [学会発表] Octyl gallate promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation. (2013)
  • 著者名/発表者名: Darrell Sawmiller, She-Qing Zhang, Kavon Rezai-Zadeh, Huayan Hou, Jared Ehrhart, Douglas Shytle, Shufeng Zhou, Brian Giunta, Takashi Mori, Jun Tan
  • 学会等名: Neuroscience 13
  • 発表場所: San Diego, U.S.A.
• [学会発表] Posttreatment with cotinine improved working memory, reduced amyloid-βplaques and decreased depressive-like behavior in the Tg6799 mice (2012)
  • 著者名/発表者名: Valentina Echeverria, Ross Zeitlin, Sagar Patel, Rosalynn Solomon, Cuc Hong Tran, Jonathon Alex Grizzell, Alexandre Iarkov, Takashi Mori
  • 学会等名: Neuroscience 12
  • 発表場所: New Orleans, U.S.A
  • 年月日: 2012-10-16
• [学会発表] Autoreactive-Aβantibodies promote APPβ-secretase processing (2012)
  • 著者名/発表者名: Juan Deng, Huayan Hou, Brian Giunta, Takashi Mori, Yan-Jiang Wang, Frank Fernandez, Sascha Weggen, Wataru Araki, Demian Obregon, Jun Tan
  • 学会等名: Neuroscience 12
  • 発表場所: New Orleans, U.S.A
  • 年月日: 2012-10-15
• [学会発表] Cotinine prevented working memory loss in a mouse model of posttraumatic stress-induced cognitive impairment (2012)
  • 著者名/発表者名: Jonathon Alex Grizzell, Alexandre Iarkov, Rosalee Holmes, Takashi Mori, Valentina Echeverria
  • 学会等名: Neuroscience 12
  • 発表場所: New Orleans, U.S.A
  • 年月日: 2012-10-14
• [学会発表] Naturally-occurringβ-secretase inhibitors mitigate behavioral impairment, cerebral amyloidosis and neuroinflammation in Alzheimer transgenic mice (2012)
  • 著者名/発表者名: Terrence Town, Marie-Victoire Guillot-Sestier, Kavon Rezai-Zadeh, Jun Tan, Takashi Mori
  • 学会等名: Neuroscience 12
  • 発表場所: New Orleans, U.S.A
  • 年月日: 2012-10-13
• [学会発表] Naturally occurring β-secretase inhibitors mitigate behavioral impairment, cerebral amyloidosis and neuroinflammation in transgenic mice. (2012)
  • 著者名/発表者名: Terrence Town
  • 学会等名: Alzheimer's Association International Conference on Alzheimer's Disease
  • 発表場所: Vancouver, Canada
• [学会発表] Naturally-occurring β-secretase inhibitors mitigate behavioral impairment, cerebral amyloidosis and neuroinflammation in Alzheimer transgenic mice. (2012)
  • 著者名/発表者名: Terrence Town
  • 学会等名: Neuroscience 12
  • 発表場所: New Orleans, U.S.A.
• [学会発表] The phenolic compound ferulic acid ameliorates cognitive impairment and amyloidosis in Alzheimer mice (2011)
  • 著者名/発表者名: Takashi Mori, Kavon Rezai-Zadeh, Naoki Koyama, Yuko Horikoshi-Sakuraba, Jun Tan, Terrence Town
  • 学会等名: Neuroscience 11
  • 発表場所: Washington D.C., U.S.A
  • 年月日: 2011-11-16
• [学会発表] The phenolic compound ferulic acid ameliorates cognitive impairment and amyloidosis in Alzheimer mice (2011)
  • 著者名/発表者名: Takashi Mori, et al
  • 学会等名: 41^<th> Annual Meeting of Society for Neuroscience
  • 発表場所: Washington D.C., U.S.A.
  • 年月日: 2011-11-16
• [学会発表] Neuroinflammation as an early event and prime mover in Alzheimer's disease. (Nanosymposium) (2011)
  • 著者名/発表者名: Terrence Town, Takashi Mori, Robert M. Cohen, Jun Tan, Kavon Rezai-Zadeh
  • 学会等名: Neuroscience 11
  • 発表場所: Washington D.C., U.S.A
  • 年月日: 2011-11-14
• [学会発表] Neuroinflammation as an early event and prime mover in Alzheimer's pathobiology (2011)
  • 著者名/発表者名: Terrence Town, Takashi Mori, Robert M. Cohen, Jun Tan, Kavon Rezai-Zadeh
  • 学会等名: Alzheimer's Association International Conference on Alzheimer's Disease
  • 発表場所: Paris, France
  • 年月日: 2011-07-18
• [学会発表] Cotinine : A dual action drug with multiple benefits against Alzheimer's disease (2010)
  • 著者名/発表者名: Valentina Echeverria, Sarah Burgess, Ross Zeitlin, Arghya Barman, Garima Thakur, Hideyo Inouye, Edmundo Feris, Steven Buckingham, Daniel Kirschner, Takashi Mori, Roger Leblanc, Rajeev Prabhakar, David Sattelle, Gary W. Arendash
  • 学会等名: Alzheimer's Association International Conference on Alzheimer's Disease
  • 発表場所: Honolulu, U.S.A
  • 年月日: 2010-07-13
• [学会発表] The plant-derived polyphenol tannic acid mitigates Alzheimer's disease-like pathology (2010)
  • 著者名/発表者名: Takashi Mori, Naoki Koyama, Kavon Rezai-Zadeh, Nobuto Kakuda, Haruyasu Yamaguchi, Gary W. Arendash, Jun Tan, Terrence Town
  • 学会等名: Alzheimer's Association International Conference on Alzheimer's Disease
  • 発表場所: Honolulu, U.S.A
  • 年月日: 2010-07-13
• [学会発表] The plant-derived polyphenol tannic acid mitigates Alzheimer's disease-like pathology. (2010)
  • 著者名/発表者名: Takashi Mori
  • 学会等名: Alzheimer's Association International Conference on Alzheimer's Disease
  • 発表場所: Honolulu, U.S.A.
  • 年月日: 2010-07-13
• [図書] A naturally-occurringβ-secretase modulator, tannic acid, improves behavioral impairment and mitigates Alzheimer-like pathology, In Diet and Nutrition in Dementia and Cognitive Decline, (Martin C and Preedy V ed.) (2014)
  • 著者名/発表者名: Takashi Mori, Terrence Town
  • 出版者: Academic Press, (London), (in press)
• [図書] A naturally-occurring β-secretase modulator, tannic acid, improves behavioral impairment and mitigates Alzheimer-like pathology. In Diet and Nutrition in Dementia and Cognitive Decline, (Martin C and Preedy V ed.) (2014)
  • 著者名/発表者名: Takashi Mori, Terrence Town
  • 総ページ数: 300
  • 出版者: Academic Press