PILRA regulates microglial immunometabolism to reduce disease pathology as a candidate therapeutic target for Alzheimer’s disease

The Alzheimer’s disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. A known AD protective variant in paired immunoglobulin-like type 2 receptor alpha (PILRA), shown to reduce risk in APOE4 carriers, is enriched in a cohort of healthy centenarians; however, mechanisms underlying protective effects in microglia are undefined. Here we identify biological functions of PILRA, an ITIM-domain containing receptor, in human iPSC-derived microglia (iMG) and chimeric AD mice. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity via increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA KO also enhanced microglial chemotaxis and attenuated inflammation. We show PPAR and STAT1/3 act as critical regulators of PILRA -dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibit reduced amyloid pathology and rescued synaptic markers. A high-affinity PILRA antibody phenocopies PILRA KO; therefore, PILRA is a pharmacologically tractable therapeutic target for AD.