Departments of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
J Biol Chem. 2010 Nov 26;285(48):37405-14. doi: 10.1074/jbc.M110.149468. Epub 2010 Sep 28.
Epidemiological studies indicate that intake of statins decrease the risk of developing Alzheimer disease. Cellular and in vivo studies suggested that statins might decrease the generation of the amyloid β-peptide (Aβ) from the β-amyloid precursor protein. Here, we show that statins potently stimulate the degradation of extracellular Aβ by microglia. The statin-dependent clearance of extracellular Aβ is mainly exerted by insulin-degrading enzyme (IDE) that is secreted in a nonconventional pathway in association with exosomes. Stimulated IDE secretion and Aβ degradation were also observed in blood of mice upon peripheral treatment with lovastatin. Importantly, increased IDE secretion upon lovastatin treatment was dependent on protein isoprenylation and up-regulation of exosome secretion by fusion of multivesicular bodies with the plasma membrane. These data demonstrate a novel pathway for the nonconventional secretion of IDE via exosomes. The modulation of this pathway could provide a new strategy to enhance the extracellular clearance of Aβ.
流行病学研究表明，他汀类药物的摄入可降低患阿尔茨海默病的风险。细胞和体内研究表明，他汀类药物可能会减少β-淀粉样前体蛋白产生的淀粉样β肽（Aβ）。在这里，我们发现他汀类药物可强力刺激小胶质细胞降解细胞外 Aβ。他汀类药物依赖的细胞外 Aβ清除主要是由胰岛素降解酶（IDE）介导的，该酶通过与外泌体相关的非经典途径分泌。在外周给予洛伐他汀治疗的小鼠的血液中也观察到 IDE 分泌和 Aβ 降解的刺激。重要的是，洛伐他汀处理时 IDE 分泌的增加依赖于蛋白异戊二烯化以及多泡体与质膜融合导致的外泌体分泌的上调。这些数据表明了 IDE 通过外泌体非经典分泌的新途径。该途径的调节可能为增强细胞外 Aβ 清除提供新策略。
