Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12857/115166
Title: Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin
Authors: Zenaro, Elena 
Pietronigro, Enrica
Della Bianca, Vittorina 
Piacentino, Gennj 
Marongiu, Laura 
Budui, Simona
Turano, Ermanna 
Rossi, Barbara 
Angiari, Stefano
Dusi, Silvia 
Montresor, Alessio 
Carlucci, Tommaso
Nanì, Sara 
Tosadori, Gabriele 
Calciano, Lucia 
Catalucci, Daniele
Berton, Giorgio 
Bonetti, Bruno 
Constantin, Gabriela 
Keywords Plus: BLOOD-BRAIN-BARRIER;NONSTEROIDAL ANTIINFLAMMATORY DRUGS;TRIPLE-TRANSGENIC MODEL;TAU PATHOLOGY;A-BETA;INFLAMMATION;NEURODEGENERATION;NEUROTOXICITY;MICROGLIA;PLAQUES
Mesh headings: Alzheimer Disease;Cognition Disorders;Lymphocyte Function-Associated Antigen-1;Neutrophils
Secondary Mesh headings: Amyloid beta-Peptides;Animals;Cell Adhesion;Cell Movement;Extracellular Traps;Humans;Interleukin-17;Mice;Mice, Inbred C57BL;Mice, Transgenic;Peptide Fragments
Issue Date: Aug-2015
Publisher: NATURE PUBLISHING GROUP
Journal: Nature medicine 
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. Aβ42 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.
URI: http://hdl.handle.net/20.500.12857/115166
ISSN: 10788956
DOI: 10.1038/nm.3913
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