Elucidation of the mechanism of cerebral amyloid angiopathy by moonlighting glycolytic enzyme

Research Project

Project/Area Number	19K16919
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 51030:Pathophysiologic neuroscience-related
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)	2019-04-01 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000) Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords	アミロイドβ / 脳出血 / 認知症 / アルツハイマー病 / 脳アミロイド血管症 / アミロイドーシス / Aβ / アミロイド / 脳アミロイドアンギオパチー
Outline of Research at the Start	申請者が見出したα-エノラーゼのAβ線維形成抑制作用、Aβ線維分解作用、Aβの細胞毒性抑制作用は、脳アミロイドアンギオパチーの治療ターゲットとなる可能性がある。本研究ではこれらの成果を発展させるため「動物モデル」「培養細胞」「血清、髄液」を駆使し、α-エノラーゼのCAA病態制御に果たす役割、α-エノラーゼを用いた新しいCAAの治療法開発、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。
Outline of Final Research Achievements	In the present study, we focused on α-enolase (ENO1), well known glycolytic enzyme crucial for glucose metabolism, which is identified as up-regulated protein in brain samples from AD and CAA by proteomic analyses. Although ENO1 has been shown to possess multifunctional roles as a heat-shock protein and binding protein of cytoskeleton or chromatin structure, exact function of ENO1 in AD and CAA pathogenesis are not determined. We identified the novel function of ENO1 to directly interact with Aβ and inhibit its fibril formation, disrupt Aβ fibrils, and further to attenuate its cytotoxicities. In addition, we found that enzymatically inactivated ENO1 failed to inhibit Aβ fibril formation and disruption of Aβ fibrils. The proteolytic activity of ENO1 may underlie cytoprotective effect and clearance of Aβ from brain in AD and CAA and may be　valuable therapeutic target.
Academic Significance and Societal Importance of the Research Achievements	α-エノラーゼを治療ターゲットとした核酸医薬を開発することで、Aβタンパク質の蓄積の制御につながる治療法を創出できる可能性がある。その他、早期診断のためのバイオマーカーなど新たな医療シーズへの発展・展開が見込まれる意義ある研究成果と考える。