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

Area of Science:

• Biotechnology
• Neuroscience
• Molecular Biology

Background:

• The synthetic Notch (synNotch) receptor system enables targeted gene transcription in response to extracellular signals.
• Current synNotch applications are limited to membrane-bound targets due to specific activation needs.
• The potential of synNotch to target extracellular protein aggregates, such as amyloid beta (Aβ) in Alzheimer's disease (AD), remains unexplored.

Purpose of the Study:

• To engineer and validate a synNotch receptor capable of targeting extracellular amyloid beta (Aβ) aggregates.
• To assess the ability of the engineered synNotch system to induce the production of AD-targeting antibodies.

Main Methods:

• Engineered an Aβ-targeting synNotch receptor.
• Designed the synNotch system to control the production of chimeric Lecanemab or Aducanumab antibodies.
• Utilized NIH 3T3 cells expressing the synNotch system for detection and response assays.

Main Results:

• NIH 3T3 cells expressing the engineered synNotch receptor successfully detected extracellular Aβ aggregates.
• The synNotch system responded to Aβ aggregates by synthesizing and secreting chimeric Aducanumab or Lecanemab.
• Demonstrated successful targeting of extracellular protein aggregates by the synNotch system.

Conclusions:

• The study successfully extended the application of synNotch technology beyond membrane-bound targets.
• The engineered synNotch system can target extracellular protein aggregates like Aβ, opening new avenues for AD research.
• This advancement offers significant benefits for research in neurodegenerative diseases and protein aggregate targeting.