sAPPα acts as an endogenous ligand for TREM2 to regulate microglial survival and inflammatory responses in Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial functions in Alzheimer's disease, whereas soluble amyloid precursor protein alpha (sAPPα) has neuroprotective effects. Whether sAPPα directly interacts with TREM2 remains unclear. Single-cell RNA sequencing data from wild-type and APP/PS1 mouse cortices and bulk RNA-seq data (GSE18309) were analyzed. Solid-phase binding, pull-down, and co-immunoprecipitation assays were used to examine TREM2-sAPPα binding and map the interacting regions. LPS-stimulated BV-2 cells were used to assess the effects of TREM2 knockdown and sAPPα supplementation on viability, apoptosis, invasion, phagocytosis, cytokine production, and polarization. A TREM2-positive microglial subpopulation was more abundant in the APP/PS1 dataset and showed relatively restrained inflammatory signaling. Cell-cell communication analysis predicted enhanced APP-(TREM2+TYROBP) signaling. Biochemical assays confirmed direct binding between TREM2 and sAPPα. The TREM2 51-71 amino acid region and the APP E1+Ac fragment contributed to this interaction, whereas TREM2 variants Y38C, R47H, R62H, and T66M reduced binding affinity. TREM2 knockdown aggravated LPS-induced loss of viability, apoptosis, inflammatory cytokine production, and M1-like polarization in BV-2 cells. Exogenous sAPPα reversed these changes. sAPPα directly binds TREM2 and may limit excessive inflammatory activation of microglia under LPS stimulation. The TREM2-sAPPα interaction may represent a regulatory pathway relevant to Alzheimer's disease.