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<p>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&#xa0;role of telomeric DNA damage responses in Alzheimer’s disease pathogenesis, and suggest a novel target for the development of RNA-based therapies.</p>

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Telomeric DNA damage response mediates neurotoxicity of Aβ42 oligomers in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月21日

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  • Sara Sepe,
  • Federica Rey,
  • Alexandra Mancheno-Ferris,
  • Alessandra Bigi,
  • Giulia Fani,
  • Devid Damiani,
  • Matteo Cabrini,
  • Eugenia Marinelli,
  • Julio Aguado,
  • Liliana Contu,
  • Alessia di Lillo,
  • Sara Boggio,
  • Sara Tavella,
  • Ilaria Rosso,
  • Stefano Gustincich,
  • Fabrizio Chiti,
  • Fabrizio d’Adda di Fagagna

摘要

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.