Significance and clinical application of GDF15 in mitochondrial dysfunction in Alzheimer's disease

• Project/Area Number: 17K15887
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: University of Tsukuba
• Principal Investigator: Tsuji Hiroshi 筑波大学, 医学医療系, 講師 (40633970)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: GDF15 / GDF-15 / リンパ腫 / 多発性硬化症 / Tumafactive lesion / PGRN / ミトコンドリア / アルツハイマー病 / 神経変性疾患 / パーキンソン病 / 認知症

Outline of Final Research Achievements

A secreted protein called GDF15 (Growth/differentiation factor 15) reflects mitochondrial function. Elucidating the dynamics of GDF15 in biological samples may clarify AD and mitochondrial dysfunction. We, therefore, measured and compared GDF15 levels in cerebrospinal fluid in multiple sclerosis (MS), central nervous system lymphoma (CNS lymphoma), and glioma. The cerebrospinal fluid GDF15 values of 9 patients with multiple sclerosis, 6 patients with CNS lymphoma, and 3 patients with glioblastoma were 320.4±246.5 pg/ml, 419.5±237.6 pg/ml, and 471.0±237.6 pg/ml, respectively. The values were significantly higher in CNS lymphoma and glioma compared with MS (P ＝ 0.009, P = 0.037). Based on the above results, GDF15 is useful in distinguishing between MS and malignant diseases of the central nervous system. These results show that GDF15 can be measured in clinical samples and used for neurodegenerative diseases such as Alzheimer’s disease.

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー型認知症は，高齢化社会と共に罹患者数が増加傾向にあり，社会問題となっている．アルツハイマー病の原因にアミロイドβ蛋白が，疾患感受性遺伝子にアポリポ蛋白Eのアイソフォームが関わってくる．これらの蛋白は神経細胞内の酸化ストレスに影響され，その細胞内の酸化を担うのがミトコンドリアである．最近，ミトコンドリア機能異常がアルツハイマー病の発症と関係があることが報告されており，またミトコンドリア機能を反映するのが，GDF15という分泌性蛋白である．本研究ではGDF15を髄液で測定できることが明らかとなり、臨床応用が可能となった。

Research Products

• [Journal Article] Superficial siderosis of the central nervous system despite successful treatment of cerebral arteriovenous malformation: A case report (2020)
  • Author(s): Tsuji Hiroshi、Ouchi Shogo、Okune Sho、Yamazaki Daichi、Hayakawa Mikito、Sato Masayuki、Masuda Yosuke、Hosaka Ai、Tamaoka Akira
  • Journal Title: Interdisciplinary Neurosurgery Volume: 20 Pages: 100671-100671
  • DOI: 10.1016/j.inat.2020.100671
  • NAID: 120007159559
  • Peer Reviewed / Open Access
• [Journal Article] Pembrolizumab treatment of metastatic urothelial cancer without exacerbating myasthenia gravis (2020)
  • Author(s): Ishii Akiko、Yokoyama Minato、Tsuji Hiroshi、Fujii Yasuhisa、Tamaoka Akira
  • Journal Title: eNeurologicalSci Volume: 19 Pages: 100236-100236
  • DOI: 10.1016/j.ensci.2020.100236
  • Peer Reviewed / Open Access
• [Journal Article] GDF-15, a mitochondrial disease biomarker, is associated with the severity of multiple sclerosis (2019)
  • Author(s): Nohara S, Ishii A, Yamamoto F, Yanagiha K, Moriyama T, Tozaka N, Miyake Z, Yatsuga S, Koga Y, Hosaka T, Terada M, Yamaguchi T, Aizawa S, Mamada N, Tsuji H, Tomidokoro Y, Nakamagoe K, Ishii K, Watanabe M, Tamaoka A
  • Journal Title: Journal of the neurological sciences Volume: 405 Pages: 116429-116429
  • DOI: 10.1016/j.jns.2019.116429
  • Peer Reviewed / Open Access
• [Journal Article] Alien leg phenomenon in corticobasal syndrome (2019)
  • Author(s): Nohara Seitaro、Tsuji Hiroshi、Tamaoka Akira
  • Journal Title: Journal of Clinical Neuroscience Volume: 64 Pages: 254-255
  • DOI: 10.1016/j.jocn.2019.03.053
  • Peer Reviewed
• [Journal Article] Meningeal carcinomatosis presenting with leukoencephalopathy-like imaging findings (2019)
  • Author(s): Tsuji Hiroshi、Ayako Shioya、Takayashiki Norio、Irie Toshiyuki、Itoi Satoshi、Kodama Taisuke、Kaji Yuki、Matsuoka Ryota、Mashiko Ryota、Shibata Yasushi、Ishii Akiko、Siato Yuko、Tamaoka Akira
  • Journal Title: eNeurologicalSci Volume: 14 Pages: 21-23
  • DOI: 10.1016/j.ensci.2018.11.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lateral medullary infarction in a patient with central nervous system lupus. (2017)
  • Author(s): Kato M1, Chino Y2, Sato R1, Kinoshita K1, Tsuji H3, Tokuda Y4, Tamaoka A5, Sumida T6.
  • Journal Title: Int J Rheum Dis. Volume: 20 Issue: 11 Pages: 1808-1811
  • DOI: 10.1111/1756-185x.12610
  • Peer Reviewed
• [Presentation] 多発性硬化症と腫瘍性疾患の鑑別におけるGDF-15の有用性の検討 (2022)
  • Author(s): 辻 浩史, 冨所 康志, 中馬越 清隆, 石井 亜紀子, 石井 一弘, 小川 靖裕, 玉岡 晃
  • Organizer: 第63回日本神経学会学術大会
• [Presentation] 多発性硬化症と中枢神経腫瘍性疾患の鑑別における髄液中プログラニューリン の検討 (2020)
  • Author(s): 辻 浩史
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] 辺縁系脳炎におけるGDF15およびFGF21の検討 (2017)
  • Author(s): 石井 亜紀子(筑波大学附属病院 神経内科), 山本 詞子, 野原 誠太郎, 柳葉 久実, 森山 哲也, 遠坂 直希, 三宅 善嗣, 八ツ賀 秀一, 古賀 靖敏, 保坂 孝史, 寺田 真, 山口 哲人, 相澤 哲史, 儘田 直美, 辻 浩史, 冨所 康志, 中馬越 清隆, 石井 一弘, 渡邊 雅彦, 玉岡 晃
  • Organizer: WCN2017: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] 多発性硬化症/視神経脊髄炎におけるGDF-15、FGF-21の検討 (2017)
  • Author(s): 野原 誠太郎(筑波大学 医学医療系神経内科), 石井 亜紀子, 山本 詞子, 遠坂 直希, 三宅 善嗣, 森山 哲也, 柳葉 久実, 保坂 孝史, 寺田 真, 山口 哲人, 儘田 直美, 辻 浩史, 冨所 康志, 中馬越 清隆, 石井 一弘, 渡邊 雅彦, 八ツ賀 秀一, 古賀 靖敏, 玉岡 晃
  • Organizer: WCN2017: XXIII World Congress of Neurology
  • Int'l Joint Research