Why do TREM2 therapeutic effects differ dramatically between brain and peripheral tissues?

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Description

Evidence from liver and cardiac studies was questioned for brain relevance due to tissue-specific immune environments. This fundamental gap prevents cross-tissue translation of TREM2 findings.

Source: Debate session sess_SDA-2026-04-10-trem2-ad (Analysis: trem2-ad)

Resolution criteria

Resolution requires: (1) head-to-head transcriptomic and proteomic comparison of TREM2 agonist effects in brain microglia vs liver/spleen macrophages from same AD mouse models (5xFAD or APP/PS1), measuring pathway activation signatures (TYROBP, CSF1R, complement) with >=70% pathway overlap required for cross-tissue translation; (2) patient-derived iPSC microglia xenograft experiments in humanized mouse brain vs periphery, comparing TREM2 response; (3) identification of tissue-specific modulators (blood-brain barrier factors, local cytokine milieu) that explain differential TREM2 efficacy using >=3 orthogonal assays. Single-tissue studies cannot resolve the cross-tissue efficacy discrepancy.

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