Involvment of glymphatic system in removing brain waste products in neurodegenerative diseases.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07128
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Keio University
• Principal Investigator: Misawa Hidemi 慶應義塾大学, 薬学部(芝共立), 教授 (80219617)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 筋萎縮性側索硬化症 / 凝集体 / グリアリンパ系

Outline of Final Research Achievements

Overexpression and mislocalization of aquaporin-4 (AQP4) in the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS) have previously been reported. However, how alterations of AQP4 affect interstitial bulk flow in the brain and spinal cord, the so-called glymphatic system, is unclear. In this study, we found an enhanced accumulation of disease-associated SOD1 species in SOD1G93A;AQP4－/－ mice compared with SOD1G93A mice. By directly injecting SOD1 oligomers into the spinal cord parenchyma, we observed a significantly delay in clearance of biotinylated or fluorescent-labeled SOD1 oligomers in AQP4－/－ mice than in wild-type mice. Furthermore, when we injected the fluorescent-labeled tracer protein into the cisterna magna and analyzed the tracer distribution in the spinal cord, approximately 35% processing ability was reduced in SOD1G93A mice compared to wild-type mice. These results suggest that the glymphatic system is abnormal in SOD1G93A mice.

Free Research Field

神経薬理学、病態神経科学

Academic Significance and Societal Importance of the Research Achievements

ALSの動物モデルであるSOD1G93Aマウスにおいて、AQP4による水輸送を駆動力とする老廃物排泄機構（＝グリアリンパ系）の異常が示された。この異常はAQP4の発現上昇と局在の乱れを特徴とし、AQP4欠損マウス(AQP4が存在しないこと）で観察されるグリアリンパ流の低下とは、別の病態機序であることが判明した。異常タンパク質の脳内蓄積のメカニズムとして、渇水による水流不足と、洪水による淀みの発生の２つがあることを解明した本研究は、今後の創薬戦略に有用な知見を提供するものであると考えられる。