Reducing decoys focuses fighting microglia

Abstract

Genetic variation linked to lower levels of soluble ST2, a decoy cytokine receptor for IL-33, may protect against Alzheimer's disease in female APOEε4 carriers by increasing microglial plaque removal. This discovery advances our understanding of the immune system's role in Alzheimer's disease and underscores the importance of sex-specific disease processes.

Fig. 1 |. sST2 increases Alzheimer’s disease risk by limiting microglia clearance of Aβ plaques.

Under basal conditions, IL-33 signaling via the ST2L receptor triggers microglia to ingest and degrade Aβ, a pathological protein that contributes to Alzheimer’s disease. Jiang and colleagues show how circulating soluble ST2 (sST2), a decoy IL-33 receptor that inhibits IL-33–ST2L signaling, can block microglia from clearing Aβ among women most susceptible to Alzheimer’s disease, namely, APOEε4 carriers. Conversely, the authors identify a genetic variant (rs1921622 A) that leads to decreased sST2 levels, resulting in enhanced microglial clearance of Aβ and decreased Alzheimer’s disease risk among female APOEε4 carriers. Together, results highlight a novel biomarker and target for Alzheimer’s disease that calls for future investigation. BBB, blood–brain barrier.