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

Microbes and Alzheimer’s Disease: New Findings Call for a Paradigm Change

“…Retrospective epidemiological studies linking HSV-1 and AD [5,6], as discussed earlier, coupled with a recent study by Rathore et al at Genentech reporting that genetic variants in PILRA, a receptor for HSV-1 glycoprotein B (and that affect HSV-1 viral entry into cells), are associated with AD [10], do indicate that HSV-1 may play a direct role in disease development. Interestingly, other potential HSV receptor genes are located within the APOE locus, an observation which could offer a new perspective on some of the linkages between APOE variants and AD.…”

Microglia in Alzheimer’s disease: A target for immunotherapy

“…The balance between opposing signals transmitted by these receptors controls the functional program of microglia . Recent large‐scale genome‐wide association studies (GWAS) have demonstrated that the risk of developing late‐onset AD is significantly higher for individuals with rare variants of certain immunoreceptors expressed in microglia, such as paired immunoglobulin‐like type 2 receptor α (PILRα), CD33 and triggering receptor expressed on myeloid cells 2 (TREM2) . The discovery that genetic polymorphisms of microglial immunoreceptors impact the risk for developing AD further confirms the crucial function of microglia in controlling the progression of AD pathology and pinpoints specific activating and inhibitory receptors as potential targets for therapeutic intervention.…”

“…In contrast, PILRβ associates with the signaling adaptor DAP12, which bears a tyrosine‐based activation motif that recruits the protein tyrosine kinase Syk to deliver active signals . Recent whole genome‐sequencing analysis of 1357 samples of European ancestry confirmed that PILRα G78R (rs1859788) is the likely protective variant at the 7q21 locus (rs1476679) that reduces AD risk . PILRα binds HSV‐1 glycoprotein B that has been proposed to be a key causative factor for AD .…”

“…PILRα binds HSV‐1 glycoprotein B that has been proposed to be a key causative factor for AD . G78R impairs HSV‐1 binding to PILRα, and human monocyte‐derived Mϕs expressing R78/R78 are less susceptible to HSV‐1 infection than G78/G78 Mϕs in vitro, suggesting that G78R may protect from AD by reducing HSV‐1 infection . However, the ligands of PILRα and PILRβ during AD pathogenesis and the mechanism by which PILR‐α‐ligand interaction reduces AD risk in vivo remain unclear and require more investigations.…”

Patent Highlights June–July 2019

“…Surface plasmon resonance experiments showed that PILRA R78 reduces the on-rate of ligand binding, and in vitro infection studies demonstrated reduced HSV-1 entry into human monocyte-derived macrophages. For the peer review companion paper, see Rathore et al [21]. For closely related work, see Patel et al [ The hepatic peroxisome enzyme, glycolate oxidase oxidizes glycolate to glyoxylate, which under normal physiological conditions will be detoxified to glycine by alanin:glyoxylate aminotransferase.…”