Cobas-Carreño M, Esteban-Martos A, Tomas-Gallardo L, Iribarren I, Gonzalez-Palma L, Rivera-Ramos A, Elena-Guerra J, Alarcon-Martin E, Ruiz R, Bravo M J, Venero J L, Morató X, Ruiz A, Royo J L
Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.
Proteomics and Biochemistry Unit, Andalusian Centre for Developmental Biology, CSIC- Pablo de Olavide, University, Seville, Spain.
Mol Med. 2025 May 5;31(1):171. doi: 10.1186/s10020-025-01229-y.
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.
TREM2编码一种参与疾病相关小胶质细胞（DAM）表型的小胶质细胞膜受体，其激活需要与TYROBP进行跨膜相互作用。TREM2突变是阿尔茨海默病（AD）的一个高影响风险因素，这使得TREM2成为一个重要的药物靶点。我们提出了一种细菌双杂交（B2H）系统，用于高通量筛选TREM2-TYROBP跨膜相互作用的调节剂。在一项初步研究中，分析了315种FDA批准的药物，以确定潜在的结合修饰剂。我们的流程包括多个过滤步骤，以确保候选物的特异性。筛选出了两种潜在的候选物，最终在人小胶质细胞系HMC3中进行了检测。在用抗TREM2单克隆抗体刺激后，在有候选物存在的情况下计算pSYK/SYK比值。结果，我们发现戒烟药物伐尼克兰可被视为TREM2-TYROBP相互作用的跨膜激动剂。
