Sepe Sara, Rey Federica, Mancheno-Ferris Alexandra, Bigi Alessandra, Fani Giulia, Damiani Devid, Cabrini Matteo, Marinelli Eugenia, Aguado Julio, Contu Liliana, di Lillo Alessia, Boggio Sara, Tavella Sara, Rosso Ilaria, Gustincich Stefano, Chiti Fabrizio, d'Adda di Fagagna Fabrizio
IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy.
Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy.
EMBO J. 2025 Sep 21. doi: 10.1038/s44318-025-00521-1.
Ageing is the major risk factor for Alzheimer's disease (AD), the most common neurodegenerative disorder. DNA damage is a hallmark of ageing, particularly when occurring at telomeres, genomic regions vulnerable to oxidative damage and often challenging for the cell to repair. Here, we show that brains of 3xTg-AD mice, an established AD model characterized by amyloid-β (Aβ)-induced pathology, exhibit increased activation of DNA damage response (DDR) pathways at telomeres. Exposure of mouse primary hippocampal neurons to 42-residue Aβ (Aβ42) oligomers, a significant pathogenetic contributor to AD, triggers telomeric DDR by increasing the levels of reactive oxygen species caused by calcium imbalance. Antisense oligonucleotides targeting non-coding RNAs generated at damaged telomeres in vivo (in 3xTg-AD mice) and in vitro reduce neurotoxicity in iPSC-derived human cortical neurons and mouse primary neurons while inhibiting Aβ42-induced telomeric DDR, and restore transcriptional pathways altered by Aβ and found dysregulated in AD patients. These results unveil an unexpected role of telomeric DNA damage responses in Alzheimer's disease pathogenesis, and suggest a novel target for the development of RNA-based therapies.
