Drug screening targeting TREM2-TYROBP transmembrane binding

TREM2 encodes a microglial membrane receptor involved in the disease-associated microglia (DAM) phenotype whose activation requires the transmembrane interaction with TYROBP. Mutations in TREM2 represent a high-impact risk factor for Alzheimer's disease (AD) which turned TREM2 into a significant drug target. We present a bacterial two-hybrid (B2H) system designed for high-throughput screening of modulators for the TREM2-TYROBP transmembrane interaction. In a pilot study, 315 FDA-approved drugs were analyzed to identify potential binding modifiers. Our pipeline includes multiple filtering steps to ensure candidate specificity. The screening suggested two potential candidates that were finally assayed in the human microglial cell line HMC3. Upon stimulation with anti-TREM2 mAb, pSYK/SYK ratios were calculated in the presence of the candidates. As a result, we found that varenicline, a smoking cessation medication, can be considered as a transmembrane agonist of the TREM2-TYROBP interaction.

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Publication Details

Journal
Molecular Medicine
Published
2025-05-05
DOI
https://doi.org/10.1186/s10020-025-01229-y
Citations
3
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
2.53
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article

Drug screening targeting TREM2-TYROBP transmembrane binding

Emilio Alarcón‐Martín, Rocío Ruiz, Agustı́n Ruiz, Laura Gonzalez-Palma et al.
3 citations
Molecular Medicine
Neuroinflammation and Neurodegeneration Mechanisms
2.53
article

Drug screening targeting TREM2-TYROBP transmembrane binding

Emilio Alarcón‐Martín, Rocío Ruiz, Agustı́n Ruiz, Laura Gonzalez-Palma, José Luís Royo, Xavier Morató, María José Bravo, Íñigo Iribarren, Laura Tomás‐Gallardo, José L. Venero, Alberto Rivera-Ramos, Álvaro Esteban-Martos, M. Cobas-Carreño, J. Elena-Guerra
article en
3 citations

Abstract

TREM2 encodes a microglial membrane receptor involved in the disease-associated microglia (DAM) phenotype whose activation requires the transmembrane interaction with TYROBP. Mutations in TREM2 represent a high-impact risk factor for Alzheimer's disease (AD) which turned TREM2 into a significant drug target. We present a bacterial two-hybrid (B2H) system designed for high-throughput screening of modulators for the TREM2-TYROBP transmembrane interaction. In a pilot study, 315 FDA-approved drugs were analyzed to identify potential binding modifiers. Our pipeline includes multiple filtering steps to ensure candidate specificity. The screening suggested two potential candidates that were finally assayed in the human microglial cell line HMC3. Upon stimulation with anti-TREM2 mAb, pSYK/SYK ratios were calculated in the presence of the candidates. As a result, we found that varenicline, a smoking cessation medication, can be considered as a transmembrane agonist of the TREM2-TYROBP interaction.

Molecular MedicineVol. 31(1)
Trinity College Dublin (IE), Universitat Internacional de Catalunya (ES), Centro Andaluz de Biología del Desarrollo (ES), Instituto de Biomedicina de Sevilla (ES), Hospital Universitario Virgen del Rocío (ES), Universidad de Sevilla (ES), Universidad de Málaga (ES), Universidad Pablo de Olavide (ES)
Good health and well-being
Openalex Percentile: Top 11%
Neuroinflammation and Neurodegeneration Mechanisms
2.53
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