Prevention of dementia by improving excretion of waste products from cerebrospinal fluid and brain

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09355
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Juntendo University
• Principal Investigator: Miyajima Masakazu 順天堂大学, 医学部, 教授 (60200177)
• Co-Investigator(Kenkyū-buntansha): 秋葉 ちひろ 順天堂大学, 医学部, 助教 (40837754) ; 中島 円 順天堂大学, 医学部, 准教授 (50317450)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: iNPH / CSF / DNAH14 / cilia / Alzheimer / APP / mouse

Outline of Final Research Achievements

We identified a deletion of Dnah14, which is involved in ciliary movement, from a pedigree with normal pressure hydrocephalus (NPH), and generated a Dnah14 knockout mouse (Dnah14KO). This mouse developed late-onset hydrocephalus, demonstrating abnormal ependymal ciliary movement and delayed excretion of fluorescent substances. By mating Dnah14KO with APP knock-in mice, we succeeded in creating NPH model mice with Alzheimer's disease pathology. In this mouse, it was proved that the accumulation of β-amyloid in the brain is accelerated due to the delayed excretion of waste products from the brain due to decreased ciliary motility, and cognitive function declines from a young age. Furthermore, we demonstrated that the drainage of cerebrospinal fluid (CSF) from the cerebral cistern promotes the excretion of fluorescent substances administered into the brain parenchyma. CSF drainage promotes the excretion of waste products and contributes to the prevention of cognitive dysfunction.

Free Research Field

脳神経外科学

Academic Significance and Societal Importance of the Research Achievements

特発性正常圧水頭症(iNPH)の約半数にアルツハイマー病理(AD)を認めると報告されており、脳の老廃物の排泄機構の障害が、水頭症における認知機能障害とアルツハイマー病理の進行に寄与することが推定されている。本研究結果より、加齢や飲酒などによる線毛運動の低下が脳の老廃物の蓄積を招き、認知機能障害に寄与していることが証明された。更に、髄液ドレナージにより、老廃物の排出を促進することが、認知機能障害の予防に寄与することが証明された。