Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin

Elena Zenaro, Enrica Pietronigro, Vittorina Della Bianca, Gennj Piacentino, Laura Marongiu, Simona Budui, Ermanna Turano, Barbara Rossi, Stefano Angiari, Silvia Dusi, Alessio Montresor, Tommaso Carlucci, Sara Nanì, Gabriele Tosadori, Lucia Calciano, Daniele Catalucci, Giorgio Berton, Bruno Bonetti, Gabriela Constantin

Research output: Contribution to journalArticlepeer-review

Abstract

Inflammation is a pathological hallmark of Alzheimer's disease, and innate immune cells have been shown to contribute to disease pathogenesis. In two transgenic models of Alzheimer's disease (5xFAD and 3xTg-AD mice), neutrophils extravasated and were present in areas with amyloid-β (Aβ) deposits, where they released neutrophil extracellular traps (NETs) and IL-17. Aβ 42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion to integrin ligands. In vivo, LFA-1 integrin controlled neutrophil extravasation into the CNS and intraparenchymal motility. In transgenic Alzheimer's disease models, neutrophil depletion or inhibition of neutrophil trafficking via LFA-1 blockade reduced Alzheimer's disease-like neuropathology and improved memory in mice already showing cognitive dysfunction. Temporary depletion of neutrophils for 1 month at early stages of disease led to sustained improvements in memory. Transgenic Alzheimer's disease model mice lacking LFA-1 were protected from cognitive decline and had reduced gliosis. In humans with Alzheimer's disease, neutrophils adhered to and spread inside brain venules and were present in the parenchyma, along with NETs. Our results demonstrate that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggest that the inhibition of neutrophil trafficking may be beneficial in Alzheimer's disease.

Original languageEnglish
Pages (from-to)880-886
Number of pages7
JournalNature Medicine
Volume21
Issue number8
DOIs
Publication statusPublished - Jul 27 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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