CD103–CD8+ T cells promote neurotoxic inflammation in Alzheimer’s disease via granzyme K–PAR-1 signaling
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.
Authors
- Matteo Calgaro (ORCID: https://orcid.org/0000-0002-3056-518X)
- Daniela Cecconi (ORCID: https://orcid.org/0000-0002-7314-8941)
- Monica Castellucci
- Nicola Vitulo (ORCID: https://orcid.org/0000-0002-9571-0747)
- Gabriela Constantin (ORCID: https://orcid.org/0000-0001-8978-3539)
- Elena Zenaro (ORCID: https://orcid.org/0000-0003-3928-6272)
- Jessica Brandi (ORCID: https://orcid.org/0000-0003-1643-7023)
- Eleonora Terrabuio (ORCID: https://orcid.org/0000-0002-1999-6333)
- Bruno Santos-Lima
- Enrica Pietronigro (ORCID: https://orcid.org/0000-0001-7661-2247)
- Alessandro Bani
- Gabriele Tosadori (ORCID: https://orcid.org/0000-0001-5971-4815)
- Barbara Rossi (ORCID: https://orcid.org/0000-0003-4711-1528)
- Bruno Bonetti (ORCID: https://orcid.org/0000-0002-3944-4165)
- Carlo Laudanna (ORCID: https://orcid.org/0000-0003-4050-1056)
- Gabriele Angelini
- Ermanna Turano (ORCID: https://orcid.org/0000-0002-0760-1787)
- Giulia Finotti (ORCID: https://orcid.org/0000-0002-1398-0461)
- Vittorina Della Bianca
- Nikolaos Vareltzakis
- Fabiana Mainieri
- Antonella Calore
Institutions
- University of Verona (IT)
- Azienda Ospedaliera Universitaria Integrata Verona (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1038/s41467-025-62405-6
- Citations
- 4
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.37
Funders
- Fondazione Italiana Sclerosi Multipla
- Università degli Studi di Verona