Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland.
Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland.
Elife. 2023 Sep 20;12:e83465. doi: 10.7554/eLife.83465.
The amyloid beta (Aβ) plaques found in Alzheimer's disease (AD) patients' brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic strain that expresses and secretes human Aβ. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.
阿尔茨海默病（AD）患者大脑中的淀粉样蛋白β（Aβ）斑块含有胶原蛋白，并且嵌入细胞外。已经提出了几种胶原蛋白来影响 Aβ 聚集物的形成，但它们在清除中的作用尚不清楚。为了研究胶原蛋白在体内形成和清除细胞外聚集物中的潜在作用，我们创建了一种表达和分泌人 Aβ的转基因品系。这种分泌的 Aβ 在细胞外基质的两个不同位置形成聚集物。在筛选细胞外人类 Aβ 聚集调节剂的过程中，我们发现不同的胶原蛋白可以改善或增强 Aβ 聚集。我们表明，一种解整合素和金属蛋白酶 2（ADM-2），ADAM9 的同源物，减少了细胞外 Aβ 聚集物的负荷。ADM-2 是必需且充分的，可以去除细胞外 Aβ 聚集物。因此，我们提供了体内证据表明胶原蛋白对于聚集物的形成是必需的，并且金属蛋白酶参与了细胞外 Aβ 聚集物的清除。
