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Drug screening targeting TREM2-TYROBP transmembrane binding.

M Cobas-Carreño1, A Esteban-Martos1, L Tomas-Gallardo2

  • 1Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.

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|May 5, 2025
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Summary
This summary is machine-generated.

Researchers screened FDA-approved drugs to find modulators of the TREM2-TYROBP interaction, crucial for Alzheimer's disease (AD) risk. Varenicline emerged as a potential transmembrane agonist, offering a new avenue for AD therapeutics.

Keywords:
B2HBATCHDAP12Drug screeningTREM2TYROBPVarenicline

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Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • TREM2 is a microglial receptor implicated in Alzheimer's disease (AD) pathogenesis.
  • TREM2's function relies on its interaction with TYROBP, making this interface a key drug target for AD.
  • Mutations in TREM2 are a significant risk factor for developing AD.

Purpose of the Study:

  • To develop a high-throughput screening (HTS) system to identify modulators of the TREM2-TYROBP interaction.
  • To screen FDA-approved drugs for potential binding modifiers of TREM2-TYROBP.
  • To validate identified compounds in a human microglial cell line.

Main Methods:

  • A bacterial two-hybrid (B2H) system was engineered for HTS of TREM2-TYROBP interaction modulators.
  • 315 FDA-approved drugs were screened in a pilot study.
  • Candidate specificity was ensured through multiple filtering steps.
  • Promising candidates were tested in HMC3 cells, measuring pSYK/SYK ratios upon anti-TREM2 mAb stimulation.

Main Results:

  • The B2H system successfully identified potential modulators of the TREM2-TYROBP interaction.
  • Varenicline, a smoking cessation drug, was identified as a potential transmembrane agonist.
  • Varenicline demonstrated the ability to modulate the TREM2-TYROBP interaction in human microglial cells.

Conclusions:

  • A novel B2H screening pipeline effectively identified modulators of the TREM2-TYROBP interaction.
  • Varenicline acts as a transmembrane agonist of the TREM2-TYROBP interaction.
  • This finding suggests varenicline as a potential therapeutic candidate for Alzheimer's disease.