本研究では、アルツハイマー病の発症や進行に対して抑制的に働くことが報告 されているリーリンに着目し、その不活化酵素であるADAMTS-3の阻害による アルツハイマー病態抑制効果の解明を目指した。また、成体脳でリーリンの N-t切断と不活化を担う酵素の解明を目指した。そして、以下の知見を得た。
1. ADAMTS-3を減少させれば、大脳皮質で野生型Aβの沈着を抑制あるいは
遅延できる。
2. ADAMTS-3 と同じく ADAMTS ファミリーに属する ADAMTS-2 はリーリン
N-t切断活性を示す。
3. ADAMTS-2 や ADAMTS-3 のリーリン N-t 切断活性には、Disintegrin domain や最もN末端側のThrombospondin motifが重要である。
4. 成体期ではADAMTS-3だけでなくADAMTS-2もリーリンN-t切断と不活化 を担う。
本研究はリーリンの N-t 切断のメカニズムと生理的意義の解明につながるもの であり、ADAMTS-2 および ADAMTS-3 の阻害によるアルツハイマー病の新規 治療法開発の可能性を示唆する。
引用文献
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