The late onset Alzheimer’s disease‐associated TREM2 R47H regulates susceptibility to ferroptosis

Abstract

AbstractBackgroundGenome‐wide association studies (GWAS) have identified TREM2 R47H as one of the genetic risk factors associated with late‐onset Alzheimer’s disease (LOAD). However, the mechanism underlying the contribution of this variant to the pathogenesis of, and/or the susceptibility to LOAD is still elusive.MethodDisease‐associated functional SNPs were identified and characterized by coupling Reel‐seq (Regulatory element‐sequencing), a high‐throughput mapping technique, with SDCP‐MS (SNP‐specific DNA competition pulldown‐mass spectrometry), a proteomics analysis. Ferroptosis was validated by combining MTT assay, MDA assay as well as C11‐BODIPY staining in human microglial cells.Resultrs75932628, an exonic SNP encoding for TREM2 R47H, is part of a cis‐regulatory element modulating TREM2 expression by recruiting a protein complex that contains two iron chaperons. Iron suppresses TREM2 expression by disrupting the binding of these proteins to rs75932628 and this disruption is further enhanced more by the risk allele A than the non‐risk allele G. Moreover, down‐regulation of TREM2 inhibits GPX4 expression via a TREM2‐mediated signaling pathway, resulting in ferroptosis due to accumulation of lipid peroxides.ConclusionIron, as the most abundant heavy metal in nature, induces ferroptosis by down‐regulating GPX4 via the LOAD‐associated TREM2 R47H.