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<p>Immune mechanisms contribute to the neuropathology of Alzheimer’s disease (AD) but the role of adaptive immune cells is unclear. Here we show that the brain CD8<sup>+</sup> T cell compartment is dysregulated in AD patients and in the 3xTg-AD mouse model, accumulating activated CD103<sup>–</sup> tissue-resident memory T cells that produce large amounts of granzyme K (GrK). These CD103<sup>–</sup>CD8<sup>+</sup> T cells originate from the circulation and migrate into the brain using LFA-1 integrin. Ablation of brain CD103<sup>–</sup>CD8<sup>+</sup> T cells in 3xTg-AD mice ameliorates cognitive decline and reduces neuropathology. GrK induces neuronal dysfunction and tau hyperphosphorylation in human and mouse cells via protease-activated receptor-1 (PAR-1), which is expressed at higher levels in the AD brain, revealing a key immune-mediated neurotoxic axis. We conclude that communication between CD8<sup>+</sup> T cells and the nervous system is altered in AD, paving the way for therapies targeting T cell-dependent neurotoxic inflammation.</p>

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CD103–CD8+ T cells promote neurotoxic inflammation in Alzheimer’s disease via granzyme K–PAR-1 signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月24日

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  • Eleonora Terrabuio,
  • Enrica Caterina Pietronigro,
  • Alessandro Bani,
  • Vittorina Della Bianca,
  • Carlo Laudanna,
  • Barbara Rossi,
  • Giulia Finotti,
  • Bruno Santos-Lima,
  • Elena Zenaro,
  • Ermanna Turano,
  • Gabriele Tosadori,
  • Matteo Calgaro,
  • Nicola Vitulo,
  • Monica Castellucci,
  • Daniela Cecconi,
  • Jessica Brandi,
  • Nikolaos Vareltzakis,
  • Fabiana Mainieri,
  • Antonella Calore,
  • Gabriele Angelini,
  • Bruno Bonetti,
  • Gabriela Constantin

摘要

Immune mechanisms contribute to the neuropathology of Alzheimer’s disease (AD) but the role of adaptive immune cells is unclear. Here we show that the brain CD8+ T cell compartment is dysregulated in AD patients and in the 3xTg-AD mouse model, accumulating activated CD103– tissue-resident memory T cells that produce large amounts of granzyme K (GrK). These CD103–CD8+ T cells originate from the circulation and migrate into the brain using LFA-1 integrin. Ablation of brain CD103–CD8+ T cells in 3xTg-AD mice ameliorates cognitive decline and reduces neuropathology. GrK induces neuronal dysfunction and tau hyperphosphorylation in human and mouse cells via protease-activated receptor-1 (PAR-1), which is expressed at higher levels in the AD brain, revealing a key immune-mediated neurotoxic axis. We conclude that communication between CD8+ T cells and the nervous system is altered in AD, paving the way for therapies targeting T cell-dependent neurotoxic inflammation.