Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer's disease

摘要

Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O -glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer’s disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in &50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer’s disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence. Author summary Alzheimer’s disease (AD) is a devastating neurodegenerative disorder resulting from a complex interaction of environmental and genetic risk factors. Despite considerable progress in defining the genetic component of AD risk, understanding the biology of common variant associations is a challenge. We find that PILRA G78R (rs1859788) is the likely AD risk variant from the 7q21 locus (rs1476679) and PILRA G78R reduces PILRA endogenous and exogenous ligand binding. Our study highlights a new immune signaling axis in AD and suggests a role for exogenous ligands (HSV-1). Further, we have identified that reduced function of a negative regulator of microglia and neutrophils is protective from AD risk, providing a new candidate therapeutic target.