TREM2

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is arguably the most heavily investigated microglial target in neurodegenerative disease. It operates as a critical lipid and damage-sensing receptor that orchestrates the microglial response to neurodegenerative pathologies, particularly amyloid-beta plaques and apoptotic neurons.

Upon ligand binding—frequently to APOE, lipids, or polyanionic molecules—TREM2 associates with the ITAM-containing adaptor protein TYROBP (Dap12). This initiates a potent intracellular signaling cascade through SYK and PI3K pathways. This cascade is absolutely essential for driving microglia out of their homeostatic state and into the Disease-Associated Microglia (DAM) phenotype.

In Alzheimer's disease, functional TREM2 signaling is required for microglia to physically barrier amyloid plaques, compacting them and preventing neurotoxic halo formation. Heterozygous loss-of-function variants (most notably R47H) severely impair this lipid-sensing and compaction ability, leading to diffuse, highly toxic plaques and an inflamed microenvironment, conferring a 2-4x increased risk for late-onset AD.

Conversely, complete bi-allelic loss of TREM2 or TYROBP results in Nasu-Hakola disease, driving extreme early-onset dementia and bone cysts due to complete failure of myeloid cell clearance functionality. Therapeutics currently aim to use agonistic antibodies to artificially force-start the protective DAM state early in disease progression.