JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer disease

Abstract

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimers disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that upregulation of the AP-1 subunit c-JUN triggers decondensation of genomic regions containing TEs. This leads to cytoplasmic accumulation of TE-derived RNA-DNA hybrids, activation of the cGAS-STING cascade, and increased cleaved caspase-3 levels, suggesting initiation of programmed cell death in progenitor cells and neurons. Notably, inhibiting c-JUN effectively blocks all the downstream molecular processes and rescues neuronal death and impaired neurogenesis in the AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.