CD22阻害は,老化している脳のホメオスタティックなマイクログリアルファゴシトーシスを回復させる

John V Pluvinage^1,2,3, Michael S Haney³, Benjamin A H Smith^1,4,5

¹Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.

Nature

|April 5, 2019

まとめ

研究者らは CD22受容体を抑制することで老化したマイクログリアの排泄能力が回復することを発見しましたこの介入は老いたマウスの認知機能を改善し脳の健康に対する潜在的な戦略を提供します

科学分野:

神経科学
免疫学
老化に関する研究

背景:

マイクログリアは中枢神経系 (CNS) のホメオスタシスに不可欠であり,ファゴシトーシス経由で残骸を浄化します.
マイクログリアのファゴサイト機能は年齢とともに低下し,神経変性疾患では認知機能の低下と相関する.
マイクログリア機能障害のメカニズムと回復の認知的利益はほとんど不明です.

研究の目的:

マイクログリアルファゴシトーシスの年齢に関連する遺伝的変異因子を特定する.
老化中のマイクログリア機能における CD22の役割を調査する.
認知老化に対するCD22抑制の治療の可能性を評価する.

主な方法:

CRISPR-Cas9 ノックアウトスクリーンは RNA 配列解析と組み合わせて遺伝子改変剤を特定します
抗体媒介によるCD22阻害を用いたin vivo試験
年老いたマウスの様々な残骸の微小胞症の評価.
CD22抑制後の高齢マウスの認知機能の評価

主要な成果:

B細胞受容体であるCD22は,高齢のマイクログリアで上位調節されるマイクログリアファゴシトーシスの負の調節体として特定されました.
CD22は,α2,6結合シアリック酸がファゴシトーシスに及ぼす抑制効果を媒介する.
CD22抑制は,ミエリン残留物,アミロイドβ,α- シヌクレインのクリアランスをインビボで強化した.
CD22抗体の長期的中枢神経伝達により,老いたマウスのマイクログリアがホメオスタティック状態に再プログラムされ,認知機能が改善されました.

結論:

CD22は,年齢に関連したマイクログリアルファゴシト障害の重要な媒介です.
CD22を阻害すると,微小膠の恒常機能が回復し,老化時の認知機能が向上する.
CD22を標的にすることは,年齢に関連する認知機能低下と神経変性に対する有望な治療戦略です.

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