Document Type

Article

Publication Date

12-4-2023

Comments

This article is the author's final published version in Nature Communications, Volume 14, Issue 1, December 2023, Article number 8021.

The published version is available at https://doi.org/10.1038/s41467-023-43728-8.

Copyright © The Author(s) 2023

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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Additional Files
Supplementary Information.pdf (7597 kB)
Peer Review File.pdf (2782 kB)
Reporting Summary.pdf (100 kB)
Source Data.zip (4871 kB)

PubMed ID

38049398

Language

English

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