Establishment of AD model mice harboring novel pathogenic PS1 mutation presenting "Behavioral and Psychological Symptoms of Dementia"

• Project/Area Number: 15K09840
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Sapporo Medical University
• Principal Investigator: Kawamata Jun 札幌医科大学, 医学部, 准教授 (60360814)
• Co-Investigator(Kenkyū-buntansha): 下濱 俊 札幌医科大学, 医学部, 教授 (60235687)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: アルツハイマー病 / BPSD / プレセニリン１ / トランスジェニックマウス / CRISPR/Cas9 / アルツハイマー

Outline of Final Research Achievements

We report the familial Alzheimer pedigree carrying a novel mutation, three bases deletion, which results in one amino acid deletion of PS1 (Psen1 delta p.277). To establish the adequate animal model of AD especially presenting BPSD-like symptoms, we planned to make the transgenic mice harboring the mutation using CRISPR/Cas9 method. Even after injecting more than 200 times, no living mutant mouse was obtained. Remodeling guide RNA(crRNA) results in successfully establishing the transgenic mice, which will enable the neuropathological and behavioral analysis after aging of these transgenic mice, both heterozygote and possibly homozygote.

Research Products

• [Journal Article] Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. (2017)
  • Author(s): Howard JF Jr, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, Jacob S, Vissing J, Burns TM, Kissel JT, Muppidi S, Nowak RJ, O'Brien F, Wang JJ, Mantegazza R; REGAIN Study Group.(collaborators: Kawamata J.他）
  • Journal Title: Lancet Neurol. Volume: 16 Issue: 12 Pages: 976-986
  • DOI: 10.1016/s1474-4422(17)30369-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of local cooling on excitation-contraction coupling in myasthenic muscle: Another mechanism of ice-pack test in myasthenia gravis. (2017)
  • Author(s): Yamamoto D, Imai T, Tsuda E, Hozuki T, Yamauchi R, Hisahara S, Kawamata J, Shimohama S.
  • Journal Title: Clin Neurophysiol. Volume: 128 Issue: 11 Pages: 2309-2317
  • DOI: 10.1016/j.clinph.2017.08.030
  • Peer Reviewed
• [Journal Article] Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice. (2017)
  • Author(s): Iwahara N, Hisahara S, Kawamata J, Matsumura A, Yokokawa K, Saito T, Fujikura M, Manabe T, Suzuki H, Matsushita T, Suzuki S, Shimohama S.
  • Journal Title: J Alzheimers Dis. Volume: 55 Issue: 3 Pages: 1235-1247
  • DOI: 10.3233/jad-160887
  • Peer Reviewed
• [Journal Article] Temporal Changes of CD68 and α7 Nicotinic Acetylcholine Receptor Expression in Microglia in Alzheimer’s Disease-Like Mouse Models (2015)
  • Author(s): Akihiro Matsumura, Syuuichirou Suzuki, Naotoshi Iwahara, Shin Hisahara, Jun Kawamata, Hiromi Suzuki, Ayano Yamauchi, Kazuyuki Takata, Yoshihisa Kitamura and Shun Shimohama
  • Journal Title: Journal of Alzheimer's Disease Volume: 44 Issue: 2 Pages: 409-423
  • DOI: 10.3233/jad-141572
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Evaluation of oxidative stress in the brain of a transgenic mouse model of Alzheimer disease by in vivo electron paramagnetic resonance imaging. (2015)
  • Author(s): Matsumura A, Emoto MC, Suzuki S, Iwahara N, Hisahara S, Kawamata J, Suzuki H,Yamauchi A, Sato-Akaba H, Fujii HG, Shimohama S.
  • Journal Title: Free Radic Biol Med. Volume: 85 Pages: 165-173
  • DOI: 10.1016/j.freeradbiomed.2015.04.013
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Decision making of using invasive mechanical ventilation in patients with amyotrophic lateral sclerosis in Sapporo area (2017)
  • Author(s): J. Kawamata, D. Yamamoto, T. Matsushita, A. Matsumura, S. Suzuki, S. Hisahara, S. Shimohama, E. Tsuda, R. Yamauchi
  • Organizer: XXIII World Congress of Neurology WCN2017
  • Int'l Joint Research