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.
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Neutrophils modulate Alzheimer's disease pathology.
“neutrophils have been shown to modulate Alzheimer’s disease pathology [52, 53].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [53]
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RetractedUsing blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification
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- Authors
- Zenaro, E., Pietronigro, E., Bianca, V. D., Piacentino, G., Marongiu, L., Budui, S., Turano, E., Rossi, B., Angiari, S., Dusi, S., Montresor, A., Carlucci, T., Nanì, S., Tosadori, G., Calciano, L., Catalucci, D., Berton, G., Bonetti, B., & Constantin, G.
- Affiliations
- University of Verona (IT)
- Institute of Genetic and Biomedical Research (IT)
- Corresponding author
- Constantin, Gabriela
- ORCID
- Venue
- Nature Medicine
- Published
- 2015-07-27
- Volume
- 21
- Issue
- 8
- Pages
- 880-886
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2098613848
- Cited by
- 865
- References
- 19
- Citations by year
- 2026: 76 · 2025: 111 · 2024: 132 · 2023: 113 · 2022: 90 · 2021: 90 · 2020: 61 · 2019: 59 · 2018: 55 · 2017: 46 · 2016: 29 · 2015: 3
- FWCI
- 32.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- neutrophils, Alzheimer's disease, LFA-1 integrin, neutrophil extracellular traps, IL-17, amyloid-beta, neutrophil extravasation, cognitive decline, 5xFAD mice, 3xTg-AD mice, gliosis, innate immunity, neuroinflammation, neutrophil depletion, memory
- MeSH terms
- Alzheimer Disease, Animals, Cell Adhesion, Cell Movement, Cognition Disorders, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neutrophils, Peptide Fragments, Lymphocyte Function-Associated Antigen-1, Amyloid beta-Peptides, Interleukin-17, Mice, Extracellular Traps
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