Development of prevention of Alzheimer's disease using transgenic soybean expressing amyloid beta protein

• Project/Area Number: 19K07989
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Gunma University
• Principal Investigator: Takeshi Kawarabayashi 群馬大学, 医学部, 非常勤講師 (90186156)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: アルツハイマー病 / ワクチン / 組み替え蛋白 / 認知症 / 疾患修飾療法 / アミロイド / アミロイドbeta蛋白 / 免疫療法 / ダイズ / バイオマーカー / 面期療法 / 組み替え植物 / Abeta / タウ / 組み換え植物

Outline of Research at the Start

アルツハイマー病(AD)の進行を抑制するには，認知症発症前からの免疫療法が有効と考えられている．しかし，認知症の発症予防には長期間の投与が必要であり，有効性と共に安全性や低侵襲性が重要となる．現在行われている抗体療法はその侵襲性や高額な治療費が問題となっている．我々はアミロイドbeta蛋白(Abeta)を組み込んだダイズ蛋白をダイズ種子に高容量で産生させることに成功した．組み替えダイズ蛋白をADモデルマウスに経口投与し， Abeta蓄積予防効果，記憶障害予防効果，神経細胞障害予防効果，髄膜脳炎や微小出血などの副作用の有無を検討して，有効で安全性が高く，低侵襲で安価なAD予防療法の開発を行う．

Outline of Final Research Achievements

We generated a transgenic plant-based vaccine, a soybean storage protein containing Amyloid-beta protein (Abeta) 4-10, named Abeta+ to prevent Alzheimer’s disease (AD). One mg of Abeta+ or control protein (Abeta-) was administered to TgCRND8 mice once a week from 9 weeks up to 58 weeks. Abeta+ immunization raised anti-Abeta oligomer antibodies. Spatial learning decline was prevented in the Abeta+ immunized group from 21weeks. Abeta oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Abeta oligomers in SDS extracts and Abeta smears in FA fraction of the Abeta+ treated group. There was significant inhibition of histological Abeta burden, especially in diffuse plaques, and suppression of microglial inflammation. No evidence of amyloid-related inflammatory angiopathy was observed. Abeta+ oral immunization could be a promising, cheap, and long-term safe disease-modifying therapy to prevent the pathological process in AD.

Academic Significance and Societal Importance of the Research Achievements

アミロイドbeta蛋白抗体によるアルツハイマー病(AD)の予防効果が示され、実用化されつつある。本邦でもAducanumabは承認審査中である。AD発症予防には認知症発症前からの長期の投与が必要と考えられているが、抗体療法は非常に高価で、注射のため侵襲的である。我々の開発した組み替えダイズによる経口免疫療法は有効で安全であり、さらに抗体に比べて安価に作成でき、大量生産も可能である。よってAD予防の有効な疾患修飾療法になりうると考えられる。製品化に向けて製薬会社との相談を行っている。

Research Products

• [Journal Article] Improved Neuroimaging Findings and Cognitive Function in a Case of High-altitude Cerebral Edema (2021)
  • Author(s): Urushida Y, Kikuchi Y, Shimizu C, Amari M, Kawarabayashi T, Nakamura T, Ikeda Y, Takatama M, Shoji M
  • Journal Title: Internal Medicine Volume: 60 Issue: 8 Pages: 1299-1302
  • DOI: 10.2169/internalmedicine.5747-20
  • NAID: 130008025067
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-04-15
  • Peer Reviewed
• [Journal Article] Spastic Paraplegia with Paget&apos;s Disease of Bone due to a <i>VCP</i> Gene Mutation (2021)
  • Author(s): Nakamura Takumi、Kawarabayashi Takeshi、Koh Kishin、Takiyama Yoshihisa、Ikeda Yoshio、Shoji Mikio
  • Journal Title: Internal Medicine Volume: 60 Issue: 1 Pages: 141-144
  • DOI: 10.2169/internalmedicine.4617-20
  • NAID: 130007965378
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-01-01
  • Peer Reviewed / Open Access
• [Journal Article] Age-Related Cognitive Decline and Prevalence of Mild Cognitive Impairment in the Iwaki Health Promotion Project (2021)
  • Author(s): Nakahata N, Nakamura T, Kawarabayashi T, Seino Y, Ichii S, Ikeda Y, Amari M, Takatama M, Murashita K, Ihara K, Itoh K, Nakaji S, Shoji M
  • Journal Title: Journal of Alzheimer's Disease Volume: 84 Issue: 3 Pages: 1233-1245
  • DOI: 10.3233/jad-210699
  • Peer Reviewed
• [Journal Article] Accelerated functional brain aging in pre-clinical familial Alzheimer's disease (2021)
  • Author(s): Gonneaud J, Baria AT, Pichet Binette A, Gordon BA, et al. Alzheimer’s Disease Neuroimaging Initiative (ADNI); Dominantly Inherited Alzheimer Network (DIAN) Study Group; Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT-AD) Research Group
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 5346-5346
  • DOI: 10.1038/s41467-021-25492-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IgG4-related hypothalamo-hypophysitis (2021)
  • Author(s): Urushida Y, Ishikawa D, Yanaizumi M, Nakamura T, Amari M, Kawarabayashi T, Tosaka M, Ikeda Y, Takatama M, Shoji M
  • Journal Title: eNeurologicalSci Volume: 24 Pages: 100362-100362
  • DOI: 10.1016/j.ensci.2021.100362
  • Peer Reviewed
• [Journal Article] フレイル対策におけるMCIの予防と治療 (2021)
  • Author(s): 瓦林毅 東海林幹夫
  • Journal Title: Bio Clinica Volume: 36 Pages: 22-26
• [Journal Article] Quantitative Measurement of Cerebrospinal Fluid Amyloid-β Species by Mass Spectrometry (2021)
  • Author(s): Seino Yusuke、Nakamura Takumi、Harada Tomoo、Nakahata Naoko、Kawarabayashi Takeshi、Ueda Tetsuya、Takatama Masamitsu、Shoji Mikio
  • Journal Title: Journal of Alzheimer's Disease Volume: 79 Issue: 2 Pages: 573-584
  • DOI: 10.3233/jad-200987
  • Peer Reviewed / Open Access
• [Journal Article] Amyloid and Tau Pathology Associations With Personality Traits, Neuropsychiatric Symptoms, and Cognitive Lifestyle in the Preclinical Phases of Sporadic and Autosomal Dominant Alzheimer's Disease. (2020)
  • Author(s): Pichet Binette A, Vachon-Presseau E, Morris J, Bateman R, Benzinger T, Collins DL, Poirier J, Breitner JCS, Villeneuve S; Dominantly Inherited Alzheimer Network (DIAN); PREVENT-AD Research Group.
  • Journal Title: Biol Psychiatry. Volume: S0006-3223(20) Issue: 8 Pages: 30058-5
  • DOI: 10.1016/j.biopsych.2020.01.023
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Successful basilar artery dilatation in pure bilateral cerebral peduncular infarctions using balloon angioplasty (2020)
  • Author(s): Kikuchi Yutaro、Miyamoto Naoko、Urushida Yuki、Shimizu Chisato、Amari Masakuni、Kawarabayashi Takeshi、Nakamura Takumi、Takatama Shin、Naito Isao、Ikeda Yoshio、Takatama Masamitsu、Shoji Mikio
  • Journal Title: eNeurologicalSci Volume: 21 Pages: 100282-100282
  • DOI: 10.1016/j.ensci.2020.100282
  • Peer Reviewed / Open Access
• [Journal Article] An autopsy case of primary lateral sclerosis with Alzheimer's disease. (2020)
  • Author(s): Nakamura T, Kon T, Kawarabayashi T, Wakabayashi K, Ikeda Y, Shoji M.
  • Journal Title: J Neurol Sci. Volume: 412 Pages: 116792-116792
  • DOI: 10.1016/j.jns.2020.116792
  • Peer Reviewed / Open Access
• [Journal Article] Novel ELISAs to measure total and phosphorylated tau in cerebrospinal fluid. (2020)
  • Author(s): Kawarabayashi T, Nakamura T, Miyashita K, Fukamachi I, Seino Y, Shoji M.
  • Journal Title: Neurosci Lett. Volume: 722 Pages: 134826-134826
  • DOI: 10.1016/j.neulet.2020.134826
  • Peer Reviewed
• [Journal Article] CogEvo, a cognitive function balancer, is a sensitive and easy psychiatric test battery for age-related cognitive decline. (2020)
  • Author(s): Ichii S, Nakamura T, Kawarabayashi T, Takatama M, Ohgami T, Ihara K, Shoji M.
  • Journal Title: Geriatr Gerontol Int. Volume: 20(3) Issue: 3 Pages: 248-255
  • DOI: 10.1111/ggi.13847
  • Peer Reviewed / Open Access
• [Journal Article] A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease. (2020)
  • Author(s): Barthelemy NR, Goate AM, Morris JC, Ikeuchi T, Mori H, Shimada H, Shoji M, Suzuki K, Graff-Radford NR, Salloway S, Masters CL, O'Connor A, Fox NC, Levin J, Jucker M, Gabelle A, Lehmann S, Sato C, Bateman RJ, McDade E; Dominantly Inherited Alzheimer Network ,at al.
  • Journal Title: Nat Med. Volume: 26(3) Issue: 3 Pages: 398-407
  • DOI: 10.1038/s41591-020-0781-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Perineuritis Successfully Treated with Early Aggressive Immunotherapy (2019)
  • Author(s): Nakamura T, Kawarabayashi T, Seino Y, Hirohata M, Wakabayashi K, Shoji M.
  • Journal Title: Internal Medicine Volume: 58 Issue: 19 Pages: 2875-2878
  • DOI: 10.2169/internalmedicine.2638-19
  • NAID: 130007722424
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-10-01
  • Peer Reviewed
• [Journal Article] Oral Immunization with Soybean Storage Protein Containing Amyloid-β 4-10 Prevents Spatial Learning Decline. (2019)
  • Author(s): Kawarabayashi T, Terakawa T, Takahashi A, Hasegawa H, Narita S, Sato K, Nakamura T, Seino Y, Hirohata M, Baba N, Ueda T, Harigaya Y, Kametani F, Maruyama N, Ishimoto M, St George-Hyslop P, Shoji M.
  • Journal Title: J Alzheimers Dis. Volume: 70(2) Issue: 2 Pages: 487-503
  • DOI: 10.3233/jad-190023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cerebrospinal Fluid and Plasma Biomarkers in Neurodegenerative Diseases (2019)
  • Author(s): Seino Yusuke、Nakamura Takumi、Kawarabayashi Takeshi、Hirohata Mie、Narita Sakiko、Wakasaya Yasuhito、Kaito Kozue、Ueda Tetsuya、Harigaya Yasuo、Shoji Mikio
  • Journal Title: Journal of Alzheimer's Disease Volume: 68 Issue: 1 Pages: 395-404
  • DOI: 10.3233/jad-181152
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. (2019)
  • Author(s): Dube U, Del-Aguila JL, Li Z, Budde JP, Jiang S, Hsu S, Ibanez L, Fernandez MV, Farias F, Norton J, Gentsch J, Wang F; Dominantly Inherited Alzheimer Network (DIAN), Salloway S, Masters CL, Lee JH, Graff-Radford NR, Chhatwal JP, Bateman RJ, Morris JC, Karch CM, Harari O, Cruchaga C.
  • Journal Title: Nat Neurosci. Volume: 22(11) Issue: 11 Pages: 1903-1912
  • DOI: 10.1038/s41593-019-0501-5
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Quantitative measurement of CSF Abeta species by mass spectrometry (2021)
  • Author(s): Takeshi Kawarabayashi， Yusuke Seino， Takumi Nakamura， Tomoo Harada， Naoko Nakahata，Tetsuya Ueda，Masamitsu Takatama， Mikio Shoji
  • Organizer: 第62回日本神経学会学術集会
• [Presentation] Quantitative measurement of CSF Abeta species by mass spectrometr (2021)
  • Author(s): Takeshi Kawarabayashi， Yusuke Seino， Takumi Nakamura， Tomoo Harada， Naoko Nakahata，Tetsuya Ueda，Masamitsu Takatama， Mikio Shoji
  • Organizer: Alzheimer’s Association International Conference (AAIC) 2021
• [Presentation] Mass spectrometryによるAbetaの定量 (2021)
  • Author(s): 瓦林毅， 清野祐輔， 中村琢洋, 原田朋夫， 中畑直子， 上田哲也， 高玉真光， 東海林幹夫
  • Organizer: 第41回日本認知症学会学術集
• [Presentation] 質量分析法によるアミロイドbeta蛋白定量法の開発 (2021)
  • Author(s): 瓦林毅，東海林幹夫 、甘利雅邦 、菅原隆、岩崎理、岡大典， 高玉真光
  • Organizer: 令和3年秋季群馬県医学会
• [Presentation] Oral immunization with soybean storage protein containing amyloid β4-10 prevents spatial learning decline (2020)
  • Author(s): Kawarabayashi T, Nakamura T, Takatama M, Shoji M
  • Organizer: Alzheimer’s Association International Conference (AAIC) 2020
  • Int'l Joint Research
• [Presentation] Cerebrospinal fluid and plasma biomarkers in neurodegenerative diseases. (2020)
  • Author(s): Kawarabayashi T， Seino Y， Nakamura T， Takatama M， Shoji M
  • Organizer: 61st annual meeting of Japanese society of Neurology
• [Presentation] 神経変性疾患の血漿・脳脊髄液バイオマーカー解析と新規タウELISAの開発． (2020)
  • Author(s): 瓦林毅，高玉真光，東海林幹夫
  • Organizer: 第39回日本認知症学会学術集会
• [Presentation] 神経変性疾患の脳脊髄液および血液バイオマーカーの検討． (2020)
  • Author(s): 瓦林毅，高玉真光，東海林幹夫
  • Organizer: 令和2年度秋季群馬県医学会
• [Presentation] Oral immunization with soybean storage protein containing Abeta4-10 (2019)
  • Author(s): Kawarabayashi T, Amari M, Takatama M, Shoji M
  • Organizer: Neuroscience 2019, the Society for Neuroscience, 49th Annual Meeting
  • Int'l Joint Research
• [Presentation] Oral immunization with soybean storage protein containing Abeta4-10 in Alzheimer's model mice (2019)
  • Author(s): Takeshi Kawarabayashi， Takumi Nakamura， Yusuke Seino， Mie Hirohata， Mikio Shoji
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] 組み換えダイズ蛋白によるアルツハイマー病発症予防療法の開発 (2019)
  • Author(s): 瓦林毅, 中村巧洋, 甘利雅邦, 高玉真光, 東海林幹夫
  • Organizer: 第10回日本脳血管・認知症学会総会
• [Presentation] 血漿Abeta値は腎機能により強い影響を受け，MMSEと相関する：岩木プロジェクト (2019)
  • Author(s): 中村琢洋、瓦林毅，清野祐輔，笠原浩生，池田将樹，池田佳生，東海林幹夫
  • Organizer: 第10回日本脳血管・認知症学会総会
• [Presentation] 組み替え大豆蛋白によるアルツハイマー病経口免疫の作用機序の検討 (2019)
  • Author(s): 瓦林毅，中村琢洋，清野祐輔，亀谷富由樹、池田佳生、高玉真光、東海林幹夫
  • Organizer: 第38回日本認知症学会学術集会