Development of a new therapeutic strategy for Alzheimer's disease: Exploration of amyloid-beta inhibitors derived from foods and environment enrichment therapy.

2013 Fiscal Year Final Research Report

• Project/Area Number: 22500320
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Saitama Medical University
• Principal Investigator: MORI TAKASHI 埼玉医科大学, 医学部, 准教授 (60239605)
• Co-Investigator(Kenkyū-buntansha): YAMAGUCHI Haruyasu 群馬大学, 医学部, 教授 (00158114)
• Project Period (FY): 2010-04-01 – 2014-03-31
• Keywords: 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

Research Abstract

In the clinical trials for Alzheimer's disease (AD), designer drug approaches have serious negative side effects and adverse events. Thus, we focused on a class of plant or food-derived nutraceuticals with pleiotropic activities as secretase modulators. We orally administered the phenol compounds such as tannic acid (TA) or ferulic acid (FA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes), and evaluated cognitive function and AD-like pathology. Principle findings were that TA or FA could prevent or delay 1) behavioral impairment, 2) cerebral amyloidosis, and 3) neuroinflammation. Moreover, in vitro and cell-free assays showed that the compounds effectively inhibit beta-secretase protein expression and its activity. If results in these pre-clinical mouse models translate to human AD, these findings suggest that dietary supplementation with TA or FA may prevent or delay AD evolution by modulating beta-secretase activity.

Research Products

• [Journal Article] Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice (2014)
  • Author(s): Johnathon Alex Grizzell, Alexandre Iarkov, Rosalee Holmes, Takashi Mori, Valentina Echeverria
  • Journal Title: Behav Brain Res Volume: (in press)
  • DOI: 10.1016/j.bbr.2014.03.047
  • Peer Reviewed
• [Journal Article] Mycoplasma hyorhinis markedly degradesβ-amyloid peptides in vitro and ex vivo : a novel biological approach for treating Alzheimer's disease? (2013)
  • Author(s): Ahsan Habib, Juan Deng, Huayan Hou, Qiang Zou, Brian Giunta, Yan-Jiang Wang, Demian Obregon, Darrell Sawmiller, Song Li, Takashi Mori, Jun Tan
  • Journal Title: Am J Transl Res Volume: 5 (6) Pages: 634-642
  • Peer Reviewed
• [Journal Article] Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation (2013)
  • Author(s): She-Qing Zhang, Darrell Sawmiller, Song Li, Kavon Rezai-Zadeh, Huayan Hou, Shufeng Zhou, Douglas Shytle, Brian Giunta, Frank Fernandez, Takashi Mori, Jun Tan
  • Journal Title: PLoS ONE Volume: 8 (8) Pages: e71913
  • DOI: 10.1371/journal.pone.0071913
  • Peer Reviewed
• [Journal Article] Ferulic acid is a nutraceuticalβ-secretase modulator that improves behavioral impairment and Alzheimer-like pathology in transgenic mice (2013)
  • Author(s): Takashi Mori, Naoki Koyama, Marie-Victoire Guillot-Sestier, Jun Tan, Terrence Town
  • Journal Title: PLoS ONE Volume: 8 (2) Pages: e55774
  • DOI: 10.1371/journal.pone.0055774
  • Peer Reviewed
• [Journal Article] sAPP-αmodulatesβ-secretase activity and amyloid-βgeneration (2012)
  • Author(s): Demian Obregon, Huayan Hou, Juan Deng, Brian Giunta, Jun Tian, Donna Darlington, MD Shahaduzzaman, Yuyuan Zhu, Takashi Mori, Mark P. Mattson, Jun Tan
  • Journal Title: Nat Commun Volume: 3 Pages: 777
  • DOI: 10.1038/ncomms1781
  • Peer Reviewed
• [Journal Article] Tannic acid is a naturalβ-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice (2012)
  • Author(s): Takashi Mori, Kavon Rezai-Zadeh, Naoki Koyama, Gary W. Arendash, Haruyasu Yamaguchi, Nobuto Kakuda, Yuko Horikoshi-Sakuraba, Jun Tan, Terrence Town
  • Journal Title: J Biol Chem Volume: 287 (9) Pages: 6912-6927
  • DOI: 10.1074/jbc.M111.294025
  • Peer Reviewed
• [Journal Article] Autoreactive-Aβantibodies promote APPβ-secretase processing (2012)
  • Author(s): Juan Deng, Huayan Hou, Brian Giunta, Takashi Mori, Yan-Jiang Wang, Frank Fernandez, Sascha Weggen, Wataru Araki, Demian Obregon, Jun Tan
  • Journal Title: J Neurochem Volume: 120 (5) Pages: 732-740
  • DOI: 10.1111/j.1471-4159.2011.07629.x
  • Peer Reviewed
• [Journal Article] Cotinine reduces amyloid-βaggregation and improves memory in Alzheimer's mice (2011)
  • Author(s): 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
  • Journal Title: J Alzheimer's Dis Volume: 24 (4) Pages: 817-835
  • DOI: 10.3233/JAD-2011-102136
  • Peer Reviewed
• [Journal Article] CD45 deficiency drives Aβoligomers and neuronal loss in Alzheimer's disease mice (2011)
  • Author(s): 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
  • Journal Title: J Neurosci Volume: 31 (4) Pages: 1355-1365
  • DOI: 10.1523/JNEUROSCI.3268-10.2011
  • Peer Reviewed
• [Journal Article] Granulocyte-colony stimulating factor (G-CSF) enhances recovery in mouse model of Parkinson's disease (2011)
  • Author(s): Shijie Song, Vasyl Sava, Amanda Rowe, Kunyu Lia, Chuanhai Cao, Takashi Mori, Juan Sanchez-Ramos
  • Journal Title: Neurosci Lett Volume: 487 (2) Pages: 153-157
  • DOI: 10.1016/j.neulet.2010.10.012
  • Peer Reviewed
• [Journal Article] Mutant presenilin-1 deregulated peripheral immunity exacerbates Alzheimer-like pathology (2011)
  • Author(s): 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
  • Journal Title: J Cell Mol Med Volume: 15 (2) Pages: 327-338
  • DOI: 10.1111/j.1582-4934.2009.00962.x
  • Peer Reviewed
• [Journal Article] Targeting S100B in cerebral ischemia and in Alzheimer's disease (2010)
  • Author(s): Takashi Mori, Takao Asano, Terrence Town
  • Journal Title: Cardiovasc Psychiatry Neurol Volume: Vol. 2010 Pages: 14, (Article ID 687067)
  • Peer Reviewed
• [Journal Article] GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice (2010)
  • Author(s): 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
  • Journal Title: J Alzheimer's Dis Volume: 21 (2) Pages: 507-518
  • DOI: 10.3233/JAD-2010-091471
  • Peer Reviewed
• [Journal Article] Rapamycin promotesβ-amyloid production via ADAM-10 inhibition (2010)
  • Author(s): Shequing Zhang, Jon Salemi, Huayan Hou, Yuyan Zhu, Takashi Mori, Brian Giunta, Demian F. Obregon, Jun Tan
  • Journal Title: Biochem Biophys Res Commun Volume: 398 (3) Pages: 337-341
  • DOI: 10.1016/j.bbrc.2010.06.017
  • Peer Reviewed
• [Presentation] Octyl gallate promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation (2013)
  • Author(s): Darrell Sawmiller, She-Qing Zhang, Kavon Rezai-Zadeh, Huayan Hou, Jared Ehrhart, Douglas Shytle, Shufeng Zhou, Brian Giunta, Takashi Mori, Jun Tan
  • Organizer: Neuroscience 13
  • Place of Presentation: San Diego, U.S.A
  • Year and Date: 2013-11-12
• [Presentation] Methylene blue reverses behavioral impairment and ameliorates cerebral amyloidosis in PSAPP mice (2013)
  • Author(s): Takashi Mori, Naoki Koyama, Tatsuya Segawa, Noriaki Kinoshita, Huayan Hou, Jun Tan, Terrence Town
  • Organizer: Neuroscience 13
  • Place of Presentation: San Diego, U.S.A
  • Year and Date: 2013-11-12
• [Presentation] Soluble amyloid precursor protein-αmodulatesβ-secretase activity and amyloid-βgeneration (2013)
  • Author(s): Demian Obregon, Huayan Hou, Juan Deng, Brian Giunta, Jun Tian, Donna Darlington, Md Shahaduzzaman, Takashi Mori, Mark P. Mattson, Jun Tan
  • Organizer: Neuroscience 13
  • Place of Presentation: San Diego, U.S.A
  • Year and Date: 2013-11-09
• [Presentation] Posttreatment with cotinine improved working memory, reduced amyloid-βplaques and decreased depressive-like behavior in the Tg6799 mice (2012)
  • Author(s): Valentina Echeverria, Ross Zeitlin, Sagar Patel, Rosalynn Solomon, Cuc Hong Tran, Jonathon Alex Grizzell, Alexandre Iarkov, Takashi Mori
  • Organizer: Neuroscience 12
  • Place of Presentation: New Orleans, U.S.A
  • Year and Date: 2012-10-16
• [Presentation] Autoreactive-Aβantibodies promote APPβ-secretase processing (2012)
  • Author(s): Juan Deng, Huayan Hou, Brian Giunta, Takashi Mori, Yan-Jiang Wang, Frank Fernandez, Sascha Weggen, Wataru Araki, Demian Obregon, Jun Tan
  • Organizer: Neuroscience 12
  • Place of Presentation: New Orleans, U.S.A
  • Year and Date: 2012-10-15
• [Presentation] Cotinine prevented working memory loss in a mouse model of posttraumatic stress-induced cognitive impairment (2012)
  • Author(s): Jonathon Alex Grizzell, Alexandre Iarkov, Rosalee Holmes, Takashi Mori, Valentina Echeverria
  • Organizer: Neuroscience 12
  • Place of Presentation: New Orleans, U.S.A
  • Year and Date: 2012-10-14
• [Presentation] Naturally-occurringβ-secretase inhibitors mitigate behavioral impairment, cerebral amyloidosis and neuroinflammation in Alzheimer transgenic mice (2012)
  • Author(s): Terrence Town, Marie-Victoire Guillot-Sestier, Kavon Rezai-Zadeh, Jun Tan, Takashi Mori
  • Organizer: Neuroscience 12
  • Place of Presentation: New Orleans, U.S.A
  • Year and Date: 2012-10-13
• [Presentation] The phenolic compound ferulic acid ameliorates cognitive impairment and amyloidosis in Alzheimer mice (2011)
  • Author(s): Takashi Mori, Kavon Rezai-Zadeh, Naoki Koyama, Yuko Horikoshi-Sakuraba, Jun Tan, Terrence Town
  • Organizer: Neuroscience 11
  • Place of Presentation: Washington D.C., U.S.A
  • Year and Date: 2011-11-16
• [Presentation] Neuroinflammation as an early event and prime mover in Alzheimer's disease. (Nanosymposium) (2011)
  • Author(s): Terrence Town, Takashi Mori, Robert M. Cohen, Jun Tan, Kavon Rezai-Zadeh
  • Organizer: Neuroscience 11
  • Place of Presentation: Washington D.C., U.S.A
  • Year and Date: 2011-11-14
• [Presentation] Neuroinflammation as an early event and prime mover in Alzheimer's pathobiology (2011)
  • Author(s): Terrence Town, Takashi Mori, Robert M. Cohen, Jun Tan, Kavon Rezai-Zadeh
  • Organizer: Alzheimer's Association International Conference on Alzheimer's Disease
  • Place of Presentation: Paris, France
  • Year and Date: 2011-07-18
• [Presentation] Cotinine : A dual action drug with multiple benefits against Alzheimer's disease (2010)
  • Author(s): 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
  • Organizer: Alzheimer's Association International Conference on Alzheimer's Disease
  • Place of Presentation: Honolulu, U.S.A
  • Year and Date: 2010-07-13
• [Presentation] The plant-derived polyphenol tannic acid mitigates Alzheimer's disease-like pathology (2010)
  • Author(s): Takashi Mori, Naoki Koyama, Kavon Rezai-Zadeh, Nobuto Kakuda, Haruyasu Yamaguchi, Gary W. Arendash, Jun Tan, Terrence Town
  • Organizer: Alzheimer's Association International Conference on Alzheimer's Disease
  • Place of Presentation: Honolulu, U.S.A
  • Year and Date: 2010-07-13
• [Book] 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)
  • Author(s): Takashi Mori, Terrence Town
  • Publisher: Academic Press, (London), (in press)