title: Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin.
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.
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Zenaro
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Pietronigro
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Vittorina
authors.initials: V
authors.lastname: Della Bianca
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Gennj
authors.initials: G
authors.lastname: Piacentino
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Marongiu
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Budui
authors.affiliation: Department of Neurological and Movement Sciences, Neurology Section, University of Verona, Verona, Italy.
authors.forename: Ermanna
authors.initials: E
authors.lastname: Turano
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rossi
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Angiari
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Dusi
authors.affiliation: 1] Department of Pathology and Diagnostics, University of Verona, Verona, Italy. [2] The Center for Biomedical Computing (CBMC), University of Verona, Verona, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Montresor
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Carlucci
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Nanì
authors.affiliation: 1] Department of Pathology and Diagnostics, University of Verona, Verona, Italy. [2] The Center for Biomedical Computing (CBMC), University of Verona, Verona, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Tosadori
authors.affiliation: Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Calciano
authors.affiliation: National Research Council (CNR), Institute of Genetic and Biomedical Research (IRGB), and Humanitas Research Hospital, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Berton
authors.affiliation: Department of Neurological and Movement Sciences, Neurology Section, University of Verona, Verona, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Bonetti
authors.affiliation: 1] Department of Pathology and Diagnostics, University of Verona, Verona, Italy. [2] The Center for Biomedical Computing (CBMC), University of Verona, Verona, Italy.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Constantin
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000502:physiology; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D003072:Cognition Disorders / Q000209:etiology*; D065206:Extracellular Traps; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D020381:Interleukin-17; D016169:Lymphocyte Function-Associated Antigen-1; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)