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 language | English |
|---|---|
| Pages (from-to) | 880-886 |
| Number of pages | 7 |
| Journal | Nature Medicine |
| Volume | 21 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Jul 27 2015 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. / Zenaro, Elena; Pietronigro, Enrica; Bianca, Vittorina Della; 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.
In: Nature Medicine, Vol. 21, No. 8, 27.07.2015, p. 880-886.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin
AU - Zenaro, Elena
AU - Pietronigro, Enrica
AU - Bianca, Vittorina Della
AU - Piacentino, Gennj
AU - Marongiu, Laura
AU - Budui, Simona
AU - Turano, Ermanna
AU - Rossi, Barbara
AU - Angiari, Stefano
AU - Dusi, Silvia
AU - Montresor, Alessio
AU - Carlucci, Tommaso
AU - Nanì, Sara
AU - Tosadori, Gabriele
AU - Calciano, Lucia
AU - Catalucci, Daniele
AU - Berton, Giorgio
AU - Bonetti, Bruno
AU - Constantin, Gabriela
PY - 2015/7/27
Y1 - 2015/7/27
N2 - 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.
AB - 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.
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U2 - 10.1038/nm.3913
DO - 10.1038/nm.3913
M3 - Article
C2 - 26214837
AN - SCOPUS:84939000054
VL - 21
SP - 880
EP - 886
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 8
ER -