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ApoE2,ApoE3,およびApoE4は,APP転写とAβ分泌を差異的に刺激する

Yu-Wen Alvin Huang¹, Bo Zhou², Marius Wernig³

¹Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305, USA.

|January 24, 2017

まとめ

アポリポプロテインE4 (ApoE4) は,神経細胞のアミロイドβ (Aβ) 産生を刺激することで,アルツハイマー病のリスクを有意に増加させます. これは,デュアルレウシン-ジッパーキナーゼ (DLK) 活性化を含む新しいシグナル伝達経路によって起こります.

科学分野:

神経科学
遺伝学
分子生物学

背景:

人間のアポリプロテインE (ApoE) は,ApoE2,ApoE3およびApoE4の3つの同型で存在します.
ApoE4はアルツハイマー病 (AD) の主要な遺伝的危険因子であり,ApoE2は保護性であり,ApoE3は中性である.
ApoEイソフォームがADの病原性に影響する正確なメカニズムは完全に理解されていません.

研究の目的:

ApoEイソフォームが神経細胞におけるアミロイドβ (Aβ) 産生に影響を与える分子機構を解明する.
アミロイド前駆体タンパク質 (APP) 転写のApoE介的調節に関与するシグナル伝達経路を特定する.

主な方法:

胚性幹細胞 (ES) のヒトニューロンを利用した.
ニューロンのAβ産生に対する膠質分泌のApoEアイソフォームの影響を研究した.
二重ルイシン-ジッパーキナーゼ (DLK) と下流MAPキナーゼ (MKK7,ERK1/2) の活性化を調べた.
APP転写の調節におけるAP-1転写因子の役割を評価した.

主要な成果:

アポE4 > アポE3 > アポE2の効能順でニューロンのAβ産生を刺激する.
ApoEが神経受容体に結合すると,DLK/MKK7/ERK1/2 MAPキナーゼカスケードが活性化されます.
活性化されたERK1/ 2はcFosのリン酸化とAP-1の活性化につながる.
AP-1はAPPの転写を強化し,Aβレベルを上昇させます.
このメカニズムはマウスで確認された.

結論:

ApoE同型がAPP転写とAβ合成を調節するニューロンの新しい信号伝達経路が特定されました.
アポE4イソフォームのADリスク因子としての役割は,この経路の強力な活性化に関連しています.
この経路を理解することでアルツハイマー病の治療対象となる可能性があります

キーワード:

APP についてアルツハイマー病アポエ (ApoE)Aβ について CRISPRについて CRISPRiについて DLK について MAPキナーゼシグナル伝達アミロイド前駆体タンパク質アポリプロテインE ベータ・アミロイド cFos についてデュアルレウシン-ジッパーキナーゼトランスクリプション

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