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

Chiara Scopa (), Samantha M. Barnada, Maria E. Cicardi, Mo Singer, Davide Trotti () and Marco Trizzino ()
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Chiara Scopa: Thomas Jefferson University
Samantha M. Barnada: Thomas Jefferson University
Maria E. Cicardi: Thomas Jefferson University
Mo Singer: Thomas Jefferson University
Davide Trotti: Thomas Jefferson University
Marco Trizzino: Thomas Jefferson University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s 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 the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in 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.

Date: 2023
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DOI: 10.1038/s41467-023-43728-8

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