Bergo Nicholas J, Lee Suckwon, Siebrand Cynthia J, Andersen Julie K, Walton Chaska C
bioRxiv. 2024 Oct 17:2024.10.15.618096. doi: 10.1101/2024.10.15.618096.
The synthetic Notch receptor (synNotch) system is a versatile platform that induces gene transcription in response to extracellular signals. However, its application has been largely confined to membrane-bound targets due to specific activation requirements. Whether synNotch can also target extracellular protein aggregates, such as amyloid beta (Aβ) in Alzheimer's disease (AD), is unclear. To address this, we engineered an Aβ-targeting synNotch receptor controlling the production of chimeric human-mouse versions of Lecanemab (Leqembi®) or Aducanumab (Aduhelm®), both FDA-approved antibodies for AD. We demonstrate that NIH 3T3 cells expressing this synNotch system detect and respond to extracellular Aβ aggregates by synthesizing and secreting Aducanumab or Lecanemab. These findings broaden the potential applications of synNotch, extending its targets beyond membrane-bound proteins to extracellular protein aggregates, providing obvious benefits to research in this scientific arena.
合成Notch受体（synNotch）系统是一个多功能平台，可响应细胞外信号诱导基因转录。然而，由于特定的激活要求，其应用在很大程度上局限于膜结合靶点。尚不清楚synNotch是否也能靶向细胞外蛋白质聚集体，如阿尔茨海默病（AD）中的β淀粉样蛋白（Aβ）。为了解决这个问题，我们设计了一种靶向Aβ的synNotch受体，用于控制Lecanemab（Leqembi®）或Aducanumab（Aduhelm®）的嵌合人鼠版本的产生，这两种都是FDA批准的用于治疗AD的抗体。我们证明，表达这种synNotch系统的NIH 3T3细胞通过合成和分泌Aducanumab或Lecanemab来检测细胞外Aβ聚集体并对其作出反应。这些发现拓宽了synNotch的潜在应用范围，将其靶点从膜结合蛋白扩展到细胞外蛋白质聚集体，为该科学领域的研究带来了明显的益处。
