Discovery of first-in-class small molecule TREM2 ligands as therapeutics for Alzheimer's disease (supplement)

PROJECT SUMMARY/ABSTRACT: We are requesting an administrative supplement to support the purchase of a new multi-mode plate reader capable of time-resolved fluorescence resonance energy transfer (TR-FRET) measurements, which are critical for the successful execution of our currently funded NIH R01 project [R01AG083512]. TR-FRET is a key assay platform in Aim 1 of the parent NIH award to identify the ability of TREM2-targeted small molecules to modulate key TREM2 interactions. TREM2 is a receptor expressed exclusively on microglia and plays a central role in regulating neuroinflammation and amyloid clearance in Alzheimer's disease. Two critical ligand interactions govern TREM2 function: its binding to galectin-3 (Gal-3), which promotes proinflammatory microglial activation, and its association with amyloid-β (Aβ), which enhances microglial phagocytosis of Aβ plaques. Targeting the TREM2–Gal-3 interaction offers a therapeutic avenue for dampening neuroinflammation, while stabilizing the TREM2–Aβ interaction may boost the protective clearance of pathological aggregates. Together, these interactions represent distinct and complementary strategies for modulating TREM2 activity to restore immune homeostasis and slow AD progression. Our current plate reader, which has supported these efforts for the past years, is no longer serviceable by the manufacturer. This has resulted in a significant bottleneck in our research workflow, limiting our ability to generate reproducible results, and directly affecting our ability to meet the specific aims outlined in the parent award. The acquisition of a new plate reader with TR-FRET capabilities will enable us to continue pursuing the core objectives of the funded project without delay and ensure we meet the expected scientific milestones. We are requesting funding for the full cost of the new instrument and required accessories. The current funding of the Gabr Lab, including the parent NIH award, is insufficient to cover this unanticipated expense without compromising other essential aspects of the project. However, we have sufficient institutional and grant-based support to cover all operational costs, including maintenance and routine usage, once the instrument is acquired.