Single-Cell Multi-Omic Dissection of Endogenous Retroelement Activation

Endogenous retroelements (EREs), chiefly LINE-1 (L1) retrotransposons, constitute ~40% of the human genome and are epigenetically suppressed in healthy somatic cells. Their transcriptional reactivation in the aging and Alzheimer’s disease (AD) brain has been correlated with pathology, but whether this activity originates within neurons, produces functional immunogenic ligands, and establishes a causal link to neurodegeneration remains unresolved. The primary source of sterile neuroinflammation, a hallmark of neurodegenerative disease, is unknown.