PR002323 (Project)

Description:The Alzheimer’s disease (AD) human genetic landscape identified microglia as a key disease-modifying brain cell type. A common loss-of-function coding variant in paired immunoglobulin-like type 2 receptor alpha (PILRA) associated with reduced AD risk, was found enriched in a cohort of healthy centenarians and rescued APOE4 AD risk, however the mechanisms underlying protection are undefined. Here we identify biological functions of PILRA, an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor, in human iPSC-derived microglia (iMG) and chimeric AD mice. CRISPR-mediated PILRA knockout (KO) in iMG rescued ApoE4-induced immunometabolic deficits. Moreover, loss of PILRA confers a signature of metabolic resilience in microglia with increased mitochondrial capacity in tandem with elevated antioxidants, reduced ROS and toxic lipid species. Additionally, PILRA KO iMG exhibit improved lysosomal degradation, enhanced migration, and attenuated cytokine responses. We show PPAR and STAT1/3 act as master regulators that mediate downstream signaling and regulate PILRA-dependent microglial functions. Importantly, AD mice transplanted with human PILRA KO microglia showed reduced amyloid pathology and rescued levels of synaptic markers. Finally, we identify a high-affinity human PILRA-specific antagonist antibody that phenocopies PILRA KO. Together, these findings suggest a therapeutic approach to modulate microglial immunometabolism by inhibiting PILRA, thus identifying a pharmacologically tractable target for AD.