Aβ-targeting synNotch Receptor for Alzheimer's Disease: Expanding Applications to Extracellular Protein Aggregates

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.