Strategy for overcoming Alzheimer's disease based on Zn2+-mediated cognitive decline

• Project/Area Number: 25293032
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Environmental and hygienic pharmacy
• Research Institution: University of Shizuoka
• Principal Investigator: TAKEDA ATSUSHI 静岡県立大学, 薬学部, 教授 (90145714)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 亜鉛 / アミロイドβ / 海馬 / アルツハイマー病 / 記憶 / 認知機能 / 細胞外Zn2+ / 海馬歯状回 / 亜鉛シグナリング

Outline of Final Research Achievements

The hippocampus plays important roles for spatial and declarative memory. Zn2+ is released from glutamatergic (zincergic) neuron terminals in the hippocampus and serves as a signal factor. Synaptic Zn2+ homeostasis is critical for cognitive activity in the hippocampus. Amyloid-β (Aβ) is a candidate for the pathogenesis of Alzheimer’s disease (AD) and interacts with Zn2+. Aβ1-42 interacted with extracellular Zn2+ and was taken up into dentate granule cells, followed by transiently cognitive decline via attenuated LTP. Zn-Aβ1-42-mediated cognitive decline was rescued by extracellular and intracellular Zn2+ chelators. The present study indicates that extracellular Zn2+ in the hippocampus is a therapeutic target for AD.

Research Products

• [Int'l Joint Research] The University of Melbourne(Australia)
• [Journal Article] Significance of the degree of synaptic Zn2+ signaling in cognition (2016)
  • Author(s): Atsushi Takeda and Haruna Tamano
  • Journal Title: BioMetals Volume: 29 Issue: 2 Pages: 175-185
  • DOI: 10.1007/s10534-015-9907-z
  • Peer Reviewed
• [Journal Article] Significance of synaptic Zn2+ signaling in zincergic and non-zincergic synapses in the hippocampus in cognition (2016)
  • Author(s): Hanuna Tamano, Yuta Koike, Hiroyuki Nakada, Yukina Shakushi, and Atsushi Takeda
  • Journal Title: J. Trace Elem. Med. Biol. Volume: in press Pages: 449-457
  • DOI: 10.1016/j.jtemb.2016.03.003
  • Peer Reviewed
• [Journal Article] Significance of low nanomolar concentration of Zn2+ in artificial cerebrospinal fluid (2016)
  • Author(s): Atsushi Takeda and Haruna Tamano
  • Journal Title: Mol. Neurobiol. Volume: in press
  • Peer Reviewed
• [Journal Article] Regulation of extracellular Zn2+ homeostasis in the hippocampus as a therapeutic target for Alzheimer’s disease (2015)
  • Author(s): Atsushi Takeda and Haruna Tamano
  • Journal Title: Expert Opin. Ther. Tar. Volume: 19 Issue: 8 Pages: 1-8
  • DOI: 10.1517/14728222.2015.1029454
  • Peer Reviewed
• [Journal Article] Is interaction of amyloid β-peptides with metals involved in cognitive activity? (2015)
  • Author(s): Haruna Tamano and Atsushi Takeda
  • Journal Title: Metallomics Volume: 7 Issue: 8 Pages: 1205-1212
  • DOI: 10.1039/c5mt00076a
  • Peer Reviewed
• [Journal Article] Blockade of intracellular Zn2+ signaling in the dentate gyrus erases recognition memory via impairment of maintained LTP (2015)
  • Author(s): Haruna Tamano, Tatsuya Minamino, Hiroaki Fujii, Shunsuke Takada, Masatoshi Nakamura, Masaki Ando, and Atsushi Takeda
  • Journal Title: Hippocampus Volume: 25 Issue: 8 Pages: 952-962
  • DOI: 10.1002/hipo.22418
  • Peer Reviewed
• [Journal Article] Excess influx of Zn2+ into dentate granule cells affects object recognition memory via attenuated LTP (2015)
  • Author(s): Miki Suzuki, Yuki Fujise, Yuka Tsuchiya, Haruna Tamano, Atsushi Takeda
  • Journal Title: Neurochem. Int. Volume: 87 Pages: 60-65
  • DOI: 10.1016/j.neuint.2015.05.006
  • Peer Reviewed
• [Journal Article] Influx of extracellular Zn2+ into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation (2015)
  • Author(s): Atsushi Takeda, Miki Suzuki, Munekazu Tempaku, Kazumi Ohashi, Haruna Tamano
  • Journal Title: Neuroscience Volume: 302 Pages: 209-216
  • DOI: 10.1016/j.neuroscience.2015.07.042
  • Peer Reviewed
• [Journal Article] Modification of hippocampal excitability in brain slices pretreated with low nanomolar concentration of Zn2+ (2015)
  • Author(s): Atsushi Takeda, Yukina Shakushi, and Haruna Tamano
  • Journal Title: J. Neurosci. Res. Volume: 93 Issue: 11 Pages: 1641-1647
  • DOI: 10.1002/jnr.23629
  • Peer Reviewed
• [Journal Article] Melanin production through novel processing of proopiomelanocortin in the extracellular compartment of the auricular skin of C57BL/6 mice after UV-irradiation (2015)
  • Author(s): Hiroyuki Yamamoto, Tomohiro Yamane, Kazuaki Iguchi, Kiyotaka Tanaka, Arunasiri Iddamalgoda, Keiko Unno, Minoru Hoshino, Atsushi Takeda
  • Journal Title: Sci. Rep. Volume: 2 Issue: 1 Pages: 14579-14579
  • DOI: 10.1038/srep14579
  • Peer Reviewed
• [Journal Article] Preventive effect of 3,5-dihydroxy-4-methoxybenzyl alcohol and zinc, Pacific oyster components, on glutamatergic neuron activity in the hippocampus (2015)
  • Author(s): Haruna Tamano, Yukina Shakushi, Mitsugu Watanabe, Kazumi Ohashi, Chihiro Uematsu, Tadamune Otsubo, Kiyoshi Ikeda, and Atsushi Takeda
  • Journal Title: Biol. Bul. Volume: 229 Pages: 282-288
  • Peer Reviewed
• [Journal Article] Regulation of extracellular Zn2+ homeostasis in the hippocampus as a therapeutic target for Alzheimer’s disease (2015)
  • Author(s): Atsushi Takeda and Haruna Tamano
  • Journal Title: Expert Opin. Ther. Tar. Volume: 19 Pages: 1-8
  • Peer Reviewed
• [Journal Article] The Expression of Relaxin-3 in Adipose Tissue and its Effects on Adipogenesis (2014)
  • Author(s): Hiroyuki Yamamoto, Hiromi Shimokawa, Tatsuomi Haga, Yuki Fukui, Kazuaki Iguchi, Keiko Unno, Minoru Hoshino, Atsushi Takeda
  • Journal Title: Protein Pept Lett. Volume: 21 Pages: 517-522
  • Peer Reviewed
• [Journal Article] Intracellular Zn2+ signaling in the dentate gyrus is required for object recognition memory (2014)
  • Author(s): Atsushi Takeda, Haruna Tamano, Taisuke Ogawa, Shunsuke Takada, Masatoshi Nakamura, Hiroaki Fujii, Masaki Ando
  • Journal Title: Hippocampus Volume: 24 Pages: 1404-1412
  • Peer Reviewed
• [Journal Article] Advantageous effect of theanine intake on cognition (2014)
  • Author(s): Haruna Tamano, Kotaro Fukura, Miki Suzuki, Kazuhiro Sakamoto, Hidehiko Yokogoshi, Atsushi Takeda
  • Journal Title: Nutri. Neurosci. Volume: 17 Pages: 279-283
  • Peer Reviewed
• [Journal Article] Amyloid β-mediated Zn2+ influx into dentate granule cells transiently induces a short-term cognitive deficit (2014)
  • Author(s): Atsushi Takeda, Masatoshi Nakamura, Hiroaki Fujii, Chihiro Uematsu, Tatsuya Minamino, Paul A. Adlard, Ashley I. Bush, Haruna Tamano
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e115923-e115923
  • DOI: 10.1371/journal.pone.0115923
  • Peer Reviewed / Open Access
• [Journal Article] Cognitive decline due to excess synaptic Zn2+ signaling in the hippocampus (2014)
  • Author(s): Atsushi Takeda and Haruna Tamano
  • Journal Title: Front. Aging Neurosci. Volume: 6 Pages: 26-26
  • DOI: 10.3389/fnagi.2014.00026
  • Peer Reviewed / Open Access
• [Journal Article] Intracellular Zn2+ signaling in cognition (2014)
  • Author(s): Atsushi Takeda, Hiroaki Fujii, Tatsuya Minamino, Haruna Tamano
  • Journal Title: J. Neurosci. Res. Volume: 92 Pages: 819-824
  • Peer Reviewed
• [Journal Article] Significance of Zn2+ signaling in cognition: insight from synaptic Zn2+ dysfomeostasis (2014)
  • Author(s): Atsushi Takeda
  • Journal Title: J. Trace Elem. Med. Biol. Volume: 28 Pages: 393-396
  • Peer Reviewed
• [Journal Article] Preventive effect of theanine intake on stress-induced impairments of hippocamapal long-term potentiation and recognition memory (2013)
  • Author(s): Haruna Tamano, Kotaro Fukura, Miki Suzuki, Kazuhiro Sakamoto, Hidehiko Yokogoshi, Atsushi Takeda
  • Journal Title: Brain Res. Bull. Volume: 95 Pages: 1-6
  • Peer Reviewed
• [Journal Article] Involvement of plasmin-mediated extracellular activation of progalanin in angiogenesis (2013)
  • Author(s): Hiroyuki Yamamoto, Rina Okada, Kazuaki Iguchi, Satoshi Ohno, Takashi Yokogawa, Kazuya Nishikawa, Keiko Unno, Minoru Hoshino, Atsushi Takeda
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 430 Pages: 999-1004
  • Peer Reviewed
• [Journal Article] Enhanced susceptibility to spontaneous seizures of Noda epileptic rats by loss of synaptic Zn2+ (2013)
  • Author(s): Atsushi Takeda, Masashi Iida, Masaki Ando, Masatoshi Nakamura, Haruna Tamano, Naoto Oku
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] Anti-stress effect of theanine on students during pharmacy practice: Positive correlation among salivary α-amylase activity, trait anxiety and subjective stress (2013)
  • Author(s): Keiko Unno, Naoki Tanida, Naoto Ishii, Hiroyuki Yamamoto, Kazuaki Iguchi, Minoru Hoshino, Atsushi Takeda, Hayato Ozawa, Tsutomu Ohkubo, Lekh R Juneja, Hiroshi Yamada
  • Journal Title: Pharmacol. Biochem. Behav. Volume: 111 Pages: 128-135
  • Peer Reviewed
• [Journal Article] Synaptic Zn2+ homeostasis and its significance (2013)
  • Author(s): Atsushi Takeda, Masatoshi Nakamura, Hiroaki Fujii, Haruna Tamano
  • Journal Title: Metallomics Volume: 5 Pages: 417-423
  • Peer Reviewed
• [Presentation] アミロイドβ-亜鉛形成から視た軽度認知機能障害 (2016)
  • Author(s): 武田厚司
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-28
  • Invited
• [Presentation] Bidirectional actions of hippocampal Zn2+ signaling in cognition and its decline (2015)
  • Author(s): Atsushi Takeda
  • Organizer: International Society for Trace Element Research 2015
  • Place of Presentation: Dubrovnik, Croatia
  • Year and Date: 2015-10-22
  • Int'l Joint Research / Invited
• [Presentation] Bidirectional actions of hippocampal Zn2+ signaling in cognition: its involvement in amyloid-β-induced cognitive decline (2015)
  • Author(s): Atsushi Takeda
  • Organizer: "Plenary Lecture", 2015 Spring Annual Convention of Pharmaceutical Society of Korea
  • Place of Presentation: Osong, Korea
  • Year and Date: 2015-04-24
  • Int'l Joint Research / Invited
• [Presentation] Bidirectional actions of hippocampal Zn2+ signaling in cognition: its involvement in amyloid-β-induced cognitive decline (2015)
  • Author(s): Atsushi Takeda
  • Organizer: 2015 Spring Annual Convention of Pharmaceutical Society of Korea
  • Place of Presentation: Osong, Korea
  • Year and Date: 2015-04-24
  • Invited
• [Presentation] Bidirectional actions of hippocampal Zn2+ signaling in cognition: its involvement in amyloid-β-induced cognitive decline (2015)
  • Author(s): Atsushi Takeda
  • Organizer: "Special seminar", Hallym University
  • Place of Presentation: Chuncheon, Korea
  • Year and Date: 2015-04-22
  • Int'l Joint Research / Invited
• [Presentation] Bidirectional actions of hippocampal Zn2+ signaling in cognition: its involvement in amyloid-β-induced cognitive decline (2015)
  • Author(s): Atsushi Takeda
  • Organizer: Hallym University
  • Place of Presentation: Chuncheon, Korea
  • Year and Date: 2015-04-22
  • Invited
• [Presentation] Involvement of dentate gyrus LTP maintenance in retention of space recognition memory: insight from intracellular Zn2+ signaling (2014)
  • Author(s): Atsushi Takeda
  • Organizer: International Society for Zinc Biology 2014 Meeting
  • Place of Presentation: Asilomar, CA, USA
  • Year and Date: 2014-09-17
  • Invited
• [Presentation] 海馬における亜鉛シグナリング (2014)
  • Author(s): 武田厚司
  • Organizer: 第9回近畿亜鉛栄養治療研究会
  • Place of Presentation: 大阪
  • Year and Date: 2014-08-02
  • Invited
• [Presentation] 認知記憶における海馬歯状回亜鉛シグナルの役割 (2014)
  • Author(s): 武田厚司
  • Organizer: 第25回日本微量元素学会
  • Place of Presentation: 岡山
  • Year and Date: 2014-07-03
  • Invited
• [Presentation] Intracellular Zn2+ signal in the dentate gyrus is required for object recognition memory (2014)
  • Author(s): Atsushi Takeda
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島
  • Invited
• [Presentation] Modulation of learning and memory by Zn2+ signal in the hippocampus. (2013)
  • Author(s): Atsushi Takeda
  • Organizer: Franco-Japanese Workshop on Metallomics
  • Place of Presentation: Pau, France
  • Invited
• [Presentation] Zinc Signaling in Acquring and Declining Aspects in Cognition (2013)
  • Author(s): Atsushi Takeda
  • Organizer: 10th Nordic Symposium on Trace and Mineral Elements in Health and Disease
  • Place of Presentation: Loen, Norway
  • Invited
• [Presentation] Involvement of intracellular Zn2+ signal in the dentate gyrus in cognition (2013)
  • Author(s): Atsushi Takeda
  • Organizer: Xth International Society for Trace Element Research Conference
  • Place of Presentation: Tokyo
  • Invited
• [Book] 毒性の科学 (2014)
  • Author(s): 武田厚司
  • Total Pages: 15
  • Publisher: 東京大学出版会
• [Book] Zinc Signals in Cellular Functions and Disorders (2014)
  • Author(s): Atsushi Takeda
  • Total Pages: 21
  • Publisher: Springer (Japan)
• [Book] 毒性の科学, 亜鉛シグナル異常による脳機能障害 (2014)
  • Author(s): 武田厚司
  • Total Pages: 5
  • Publisher: 東京大学出版会
• [Book] 亜鉛の機能と健康, 亜鉛シグナルからみた脳の健康 (2013)
  • Author(s): 武田厚司
  • Total Pages: 20
  • Publisher: 建帛社