1. Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin
- Author
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Lucia Calciano, Giorgio Berton, Ermanna Turano, Elena Zenaro, Gabriela Constantin, Bruno Bonetti, Laura Marongiu, Alessio Montresor, Gabriele Tosadori, Tommaso Carlucci, Enrica Caterina Pietronigro, Barbara Rossi, Daniele Catalucci, Simona Budui, Silvia Dusi, Gennj Piacentino, Sara Nani, Vittorina Della Bianca, Stefano Angiari, Zenaro, E, Pietronigro, E, Bianca, V, Piacentino, G, Marongiu, L, Budui, S, Turano, E, Rossi, B, Angiari, S, Dusi, S, Montresor, A, Carlucci, T, Nani, S, Tosadori, G, Calciano, L, Catalucci, D, Berton, G, Bonetti, B, and Constantin, G
- Subjects
Pathology ,medicine.medical_specialty ,Amyloid beta-Peptide ,Neutrophils ,Inflammation ,Mice, Transgenic ,Neuropathology ,Extracellular Traps ,General Biochemistry, Genetics and Molecular Biology ,Cognition Disorder ,Mice ,Peptide Fragment ,Alzheimer Disease ,Cell Movement ,medicine ,Cell Adhesion ,Animals ,Humans ,Lymphocyte function-associated antigen 1 ,Cognitive decline ,Alzheimer's disease, inflammation, LFA-1 integrin ,Neutrophil extravasation ,Amyloid beta-Peptides ,Animal ,business.industry ,Neutrophil ,Interleukin-17 ,LFA-1 integrin ,General Medicine ,Neutrophil extracellular traps ,Alzheimer's disease ,medicine.disease ,Extracellular Trap ,Lymphocyte Function-Associated Antigen-1 ,Peptide Fragments ,Mice, Inbred C57BL ,Gliosis ,inflammation ,Immunology ,medicine.symptom ,business ,Cognition Disorders ,Human - 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.
- Published
- 2014