Development of therapies for Alzheimer's disease with a focus on white matter function

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16574
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Nagoya University
• Principal Investigator: Kato Daisuke 名古屋大学, 医学系研究科, 講師 (10712292)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: アルツハイマー型認知症 / 白質機能障害 / オリゴデンドロサイト / 2光子顕微鏡

Outline of Final Research Achievements

The purpose of this study is to identify the functional responses of oligodendrocytes (OL), their progenitor cells (OPCs), and the morphological changes in the myelin that occur in Alzheimer's disease (AD) mice. I have elucidated the learning deficits associated with myelin impairment and the underlying neural circuitry. Therefore, calcium responses in OL/OPC were examined using two-photon microscopy. The results showed that the frequency and intensity of calcium responses in the OL/OPC were elevated in AD mice compared to WT mice. These elevations were also decreased by ATP inhibitor treatment, suggesting the involvement of ATP, which is increased by cell death. Furthermore, myelin structural evaluation by electron microscopy revealed that　microstructural changes in the myelin appear in an age- and brain region-specific manner.

Free Research Field

神経科学、神経内科

Academic Significance and Societal Importance of the Research Achievements

本研究で得られるOL/OPCの機能障害に伴う学習障害の背景にある神経回路活動に関する知見は、神経回路基盤に基づいたADの臨床症状・病態把握に役立ち、神経回路を標的とした創薬の礎となると考えられる。また、髄鞘を形成するOL/OPCの機能応答に関わる分子メカニズムを同定し、OL/OPCの機能を直接操作することで白質機能を制御する試みは、これまでにないADに対する治療法となるため社会への貢献も大きいと考えられる。また、統合失調症・多発性硬化症などの病初期から白質機能が障害される疾患に対する治療法にも適応できる可能性も高く、より広い分野・学術・社会への波及効果が期待できる。