Cholecalciferol (vitamin D3) is an agonist of the Alzheimer's disease-associated immune receptor TREM2.

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). Several TREM2 ligands are known, including charged lipids and AD-associated proteins like apolipoprotein E and amyloid-β, but the full range of endogenous ligands for TREM2 remains unknown. Here we combined virtual screening of the Human Metabolome Database with molecular dynamics simulations, binding free energy estimation, and biolayer interferometry to identify novel TREM2 ligands and map their binding sites. Cholecalciferol, the unmodified parent form of vitamin D3, emerged as a top candidate. Structural modeling indicated that cholecalciferol binds TREM2 at hydrophobic residues in an apical site previously associated with TREM2's ability to bind apolipoprotein E, and in biophysical studies cholecalciferol enhanced TREM2-apolipoprotein E binding. Functionally, cholecalciferol induced TREM2-dependent signaling in human, rat, and mouse cells. As expected with TREM2 activation, cholecalciferol stimulated phagocytosis in cultured macrophages and microglia, and induced resistance to multiple cytotoxic agents, including pathologic amyloid-β species. These findings identify a novel TREM2 ligand that may inform therapeutic strategies for AD, and a previously unrecognized receptor for cholecalciferol that provides a potential mechanistic link between vitamin D3 deficiency and increased AD risk.