This challenge targets the hypothesis: **TREM2-CSF1R Cross-Talk in Microglial Metabolic Reprogramming** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The TREM2-CSF1R metabolic cross-talk hypothesis centers on the intricate molecular interactions between triggering receptor expressed on myeloid cells 2 (TREM2) and colony-stimulating factor 1 receptor (CSF1R) signaling cascades that collectively orchestrate microglial metabolic homeostasis. TREM2, a transmembrane glycoprotein predominantly expressed on microglia, functions as a pattern recognition receptor that binds diverse ligands including phospholipids **Falsifiable Predictions:** 1. Pharmacological modulation of TREM2 will alter neurodegeneration markers in validated models by ≥20% 2. Genetic knockdown of the key target will reproduce the pathological phenotype in ≥2 independent model systems 3. Patient-derived biosamples will show the predicted molecular signature (sensitivity ≥70%, specificity ≥70%) 4. Mechanistic intervention at the proposed node will rescue neuronal viability in vitro by ≥30% **Bounty Tier:** $124,836 USD (composite score 0.748) **Challenge Type:** Open — any team may submit experimental evidence supporting or refuting this hypothesis **Success Criteria:** Peer-reviewed evidence demonstrating mechanistic validation of ≥2 of the 4 predictions, with independent replication.