The role of SRPX1 in cerebral amyloid angiopathy

• Project/Area Number: 17H06972
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Kumamoto University
• Principal Investigator: Inoue Yasuteru 熊本大学, 大学院生命科学研究部(医), 特任助教 (00806408)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: アミロイドーシス / 脳アミロイドアンギオパチー / 脳アミロイド血管症 / 脳出血 / アミロイドベータ / 認知症 / アミロイドβ / アポトーシス / アルツハイマー病 / プロテオミクス / 脳血管障害 / アミロイドアンギオパチー / SRPX1

Outline of Final Research Achievements

Several molecules have reportedly co-accumulated with tissue amyloid deposits in patients with amyloidosis. Co-accumulating molecules may be a key-molecule in amyloidosis therapy and diagnosis. In CAA, however, molecules that co-accumulate with cerebrovascular Aβ deposits are unknown. To identify the key molecules in CAA, we used laser capture microdissection to perform proteomic analyses with cerebral blood vessels obtained from CAA cases. Last year, we reported highly expressed co-accumulating molecules in CAA-affected vessels derived from human brain samples. The present study proposal focuses on Enzyme X, a highly up-regulated molecule in CAA in our prior research. We found that Enzyme X inhibits Amyloid beta fibril formation, degrades Aß fibrils, and attenuates Amyloid beta-mediated cytotoxicities. From these results, we hypothesized that Enzyme X may be a novel therapeutic target for CAA and AD.

Academic Significance and Societal Importance of the Research Achievements

Enzyme Xは生来人類が備え持つ酵素であり、そのCAAやADに対する病態抑制効果に着目した治療応用研究は、その安全性からも研究の持つ意義が大きいと考える。Enzyme XによるCAAの病態改善効果の分子基盤が解明されれば、同様のタンパク沈着を主体とするパーキンソン病、プリオン病などの他の神経変性疾患に対し応用・発展できる可能性がある。本研究ではこれらの研究成果を基にEnzyme XのCAA病態制御機構の解明、Enzyme Xを用いた新しいCAAの治療法開発、早期診断など臨床応用へ将来的に発展させるための基盤となる研究を行う。

Research Products

• [Journal Article] Apolipoprotein E and clusterin inhibit the early phase of amyloid-β aggregation in an in vitro model of cerebral amyloid angiopathy (2019)
  • Author(s): Endo Y, Hasegawa K, Nomura R, Arishima H, Kikuta K, Yamashita T, Inoue Y, Ueda M, Ando Y, Wilson MR, Hamano T, Nakamoto Y, Naiki H.
  • Journal Title: Acta Neuropathologica Communications Volume: 7 Issue: 1 Pages: 12-12
  • DOI: 10.1186/s40478-019-0662-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1 (2019)
  • Author(s): Tasaki M, Ueda M, Hoshii Y, Mizukami M, Matsumoto S, Nakamura M, Yamashita T, Ueda A, Misumi Y, Masuda T, Inoue Y, Torikai T, Nomura T, Tsuda Y, Kanenawa K, Isoguchi A, Okada M, Matsui H, Obayashi K, Ando Y.
  • Journal Title: The Journal of Pathology Volume: 247 Issue: 4 Pages: 444-455
  • DOI: 10.1002/path.5203
  • Peer Reviewed
• [Journal Article] Extreme Adhesion Activity of Amyloid Fibrils Induces Subcutaneous Insulin Resistance (2018)
  • Author(s): Nakamura M, Misumi Y, Nomura T, Oka W, Isoguchi A, Kanenawa K, Masuda T, Yamashita T, Inoue Y, Ando Y, Ueda M.
  • Journal Title: Diabetes Volume: 68 Issue: 3 Pages: 609-616
  • DOI: 10.2337/db18-0846
  • Peer Reviewed
• [Book] 医学のあゆみ (2018)
  • Author(s): 井上泰輝, 植田光晴
  • Total Pages: 2
  • Publisher: 医歯薬出版株式会社