Model animals by nonhuman primate for Alzheimer disease, hyper expression of mutant amyloid precursor protein and formation of senile plaques in the brain

• Project/Area Number: 23300155
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Shiga University of Medical Science
• Principal Investigator: NAKAMURA Shinichiro 滋賀医科大学, 動物生命科学研究センター, 准教授 (50307980)
• Co-Investigator(Kenkyū-buntansha): OKADA Takashi 日本医科大学, 医学研究科, 教授 (00326823) ; NISHIMURA Masaki 滋賀医科大学, 分子神経科学研究センター, 教授 (40322739) ; MATSUO Akinori 滋賀医科大学, 分子神経科学研究センター, 助教 (20324585) ; 岡田 尚巳 日本医科大学, 医学(系)研究科(研究院), 教授 (00326828)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000); Fiscal Year 2014: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2013: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2012: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2011: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: アルツハイマー病 / アミロイドβ / アデノ随伴ウイルス / カニクイザル / AAVベクター / 霊長類 / 疾患モデル / アミロイドβ蛋白

Outline of Final Research Achievements

It takes more than 20 years to build up Alzheimer-related histological features in the brains of nonhuman primates. Therefore, an artificial primate model would be required to improve it. We planned that Adeno-associated virus vector recombined with a candidate gene (Sweden type APP) for onset of Alzheimer disease inoculated to 3 months old mice. As a result, the inoculated mice increased to secrete A beta 1-40 more than control mice. Since this recombined viral vector possesses an ability of hyper expression of A beta, we attempt now to inoculate the vector and are checking the effect of it using cynomolgus monkeys.

Research Products

• [Journal Article] The FAM3 superfamily member ILEI ameliorates Alzheimer's disease-like pathology by destabilizing the penultimate amyloid-beta precursor. (2014)
  • Author(s): Hasegawa, H., L. Liu, I. Tooyama, S. Murayama and M. Nishimura
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 3917-3917
  • DOI: 10.1038/ncomms4917
  • Peer Reviewed
• [Journal Article] Suppression of leaky expression of adenovirus genes by insertion of microRNA-targeted sequences in the replication-incompetent adenovirus vector genome (2014)
  • Author(s): Sakurai F, Shimizu K, Tomita K, Nagamoto Y, Nakamura S, Katayama K, Tachibana M, Kawabata K, Mizuguchi H.
  • Journal Title: Mol Ther Methods Clin Dev Volume: 1 Pages: 14035-14035
  • DOI: 10.1038/mtm.2014.35
  • Peer Reviewed / Open Access
• [Journal Article] Age-related modulation of γ-secretase activity in non-human primate brains (2012)
  • Author(s): Nishimura M
  • Journal Title: J Neurochem Volume: 123 Issue: 1 Pages: 21-28
  • DOI: 10.1111/j.1471-4159.2012.07884.x
  • Peer Reviewed
• [Journal Article] Human Neural Stem Cells Overexpressing Choline Acetyltransferase Restore Cognitive Function of Kainic Acid-Induced Learning and Memory Deficit Animals (2012)
  • Author(s): Park D, Joo SS, Kim TK, Lee SH, Kang H, Lee HJ, Lim I, Matsuo A, Tooyama I, Kim YB, Kim SU
  • Journal Title: Cell Transplantaion Volume: 36(5) Issue: 1 Pages: 365-371
  • DOI: 10.3727/096368911x586765
  • Peer Reviewed
• [Journal Article] Human neural stem cells overexpressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction (2012)
  • Author(s): Park D, Lee HJ, Joo SS, Lim I, Matsuo A, Tooyama I, Kim YB, Kim SU
  • Journal Title: Experimental Neurology Volume: 234(2) Issue: 2 Pages: 521-526
  • DOI: 10.1016/j.expneurol.2011.12.040
  • Peer Reviewed
• [Journal Article] Aged vervet monkeys developing transthyretin amyloidosis with the human disease-causing Ile 122 allele : A valid pathological model of the human disease (2012)
  • Author(s): Ueda M
  • Journal Title: Lab Invest Volume: 92 Issue: 3 Pages: 474-84
  • DOI: 10.1038/labinvest.2011.195
  • Peer Reviewed
• [Journal Article] γセクレターゼ複合体に作用しAβ産生を制御する内在性タンパク質 (2012)
  • Author(s): 西村正樹
  • Journal Title: Dementia Japan Volume: 26(1) Pages: 44-50
• [Journal Article] Potent amyloidogenicity and pathogenicity of Aβ43 (2011)
  • Author(s): Takashi Saito, Takahiro Suemoto, Nathalie Brouwers, Kristel Sleegers, Satoru Funamoto, Naomi Mihira, Yukio Matsuba, Kazuyuki Yamada, Per Nilsson, Jiro Takano, Masaki Nishimura, Nobuhisa Iwata, Christine Van Broeckhoven, Yasuo Ihara, Takaomi C Saido
  • Journal Title: Nature Neuroscience Volume: 14 Issue: 8 Pages: 1023-1032
  • DOI: 10.1038/nn.2858
  • NAID: 120006985066
  • Peer Reviewed
• [Journal Article] Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease : evidence for γ-secretase dysfunction (2011)
  • Author(s): Hata S
  • Journal Title: Ann.Neurol. Volume: 69 Issue: 6 Pages: 1026-1031
  • DOI: 10.1002/ana.22343
  • Peer Reviewed
• [Presentation] 霊長類特有の加齢性病変-霊長類が背負った老化の代償- (2014)
  • Author(s): 中村紳一朗
  • Organizer: 第30回日本霊長類学会大会
  • Place of Presentation: 大阪市
  • Year and Date: 2014-07-06
  • Invited
• [Presentation] アルツハイマー経口ワクチン接種の老齢カニクイザルにおけるアミロイドβタンパクの画像解析 (2011)
  • Author(s): 中村紳一朗、松本信英、鳥居隆三、田平武
  • Organizer: 第152回日本獣医学会学術集会
  • Place of Presentation: 堺市
  • Year and Date: 2011-09-19
• [Presentation] Interaction of p24a2 with γ-secretase complex attenuates γ-cleavage of APP (2011)
  • Author(s): Nishimura M, Liu L, Hasegawa H
  • Organizer: Alzheimer's Association International 2011 Conference on Alzheimer's Disease
  • Place of Presentation: フランス、パリ
  • Year and Date: 2011-07-18
• [Book] AMYLOIDOSIS ; Transthyretin amyloidosis in aged vervet monkeys, as a candidate for the spontaneous animal model of senile systemic amyloidosis(Sarantseva S.ed.) (2011)
  • Author(s): Nakamura S, Ueda M, Ageyama N, Ando Y, Torii R
  • Total Pages: 10
  • Publisher: INTECH
• [Remarks]
  • URL: http://www.shiga-med.ac.jp/db/web/0045629348pub.html