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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Figure 1: Neutrophils adhere in brain vessels and migrate into the parenchyma during the early stage of disease.
Figure 2: Neutrophils traffic into the brain and Aβ triggers neutrophil adhesion.
Figure 3: LFA-1 integrin is necessary for neutrophil trafficking into the brain in Alzheimer's disease models.
Figure 4: Neutrophil depletion improves cognitive function and reduces Alzheimer's disease-like pathology in 3xTg-AD mice.
Figure 5: LFA-1 integrin blockade or genetic deficiency is protective in 3xTg-AD mice.
Figure 6: Neutrophils adhere in brain vessels, are present in the parenchyma and produce NETs in the brains of individuals with Alzheimer's disease.

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Acknowledgements

We thank C. Laudanna (University of Verona) for providing the reagents to measure LFA-1 integrin affinity in human neutrophils. This work was supported by funding under the European Research Council grant 261079-NEUROTRAFFICKING (G.C.), Fondazione Cariverona (G.C.) and the European Community FP7 grant 282095-TARKINAID (G.B.). S.D. received a fellowship from the Fondazione Italiana Sclerosi Multipla, Genoa, Italy.

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Contributions

G.C., E.Z and E.P. designed the experiments and analyzed the data. E.Z., E.P., V.D.B., G.P., S.B., E.T., B.R., S.A., S.D., A.M., L.M. and T.C. performed the experiments. G.B. and S.N. provided expertise in neutrophil extracellular traps. D.C. provided 129/C57BL6 mice. G.T. and L.C. analyzed the proximity between amyloid plaques and MPO+ cells. B.B. provided human tissue samples. E.Z. and G.C. wrote the paper.

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Correspondence to Gabriela Constantin.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Table 1 (PDF 9790 kb)

Source data to Supplementary Figures 1–6

41591_2015_BFnm3913_MOESM51_ESM.mov

Neutrophils migrate into the brain parenchyma of 5xFAD mice. (MOV 1658 kb)

Neutrophils migrate into the brain parenchyma of 5xFAD mice. (MOV 1658 kb)

41591_2015_BFnm3913_MOESM52_ESM.mov

Neutrophils interact with the vascular endothelium in 5xFAD mice. (MOV 1672 kb)

Neutrophils interact with the vascular endothelium in 5xFAD mice. (MOV 1672 kb)

41591_2015_BFnm3913_MOESM53_ESM.mov

Neutrophils show strong directional movement in the brain parenchyma of 5xFAD mice. (MOV 1589 kb)

Neutrophils show strong directional movement in the brain parenchyma of 5xFAD mice. (MOV 1589 kb)

41591_2015_BFnm3913_MOESM54_ESM.mov

Neutrophils show non-directional movement inside the brain parenchyma. (MOV 815 kb)

Neutrophils show non-directional movement inside the brain parenchyma. (MOV 815 kb)

41591_2015_BFnm3913_MOESM55_ESM.mov

Neutrophil infiltration into the brain parenchyma occurs preferentially in Aβ-rich areas. (MOV 2004 kb)

Neutrophil infiltration into the brain parenchyma occurs preferentially in Aβ-rich areas. (MOV 2004 kb)

41591_2015_BFnm3913_MOESM56_ESM.mov

Vascular Aβ deposition promotes neutrophil adhesion in cortical vessels of 5xFAD mice. (MOV 2279 kb)

Vascular Aβ deposition promotes neutrophil adhesion in cortical vessels of 5xFAD mice. (MOV 2279 kb)

41591_2015_BFnm3913_MOESM57_ESM.mov

LFA-1 integrin is necessary for neutrophil infiltration into the brain parenchyma of 5xFAD mice. (MOV 2221 kb)

LFA-1 integrin is necessary for neutrophil infiltration into the brain parenchyma of 5xFAD mice. (MOV 2221 kb)

41591_2015_BFnm3913_MOESM58_ESM.mov

Blocking LFA-1 integrin inhibits the motility of neutrophils within the brain parenchyma of 5xFAD mice. (MOV 1616 kb)

Blocking LFA-1 integrin inhibits the motility of neutrophils within the brain parenchyma of 5xFAD mice. (MOV 1616 kb)

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Zenaro, E., Pietronigro, E., Bianca, V. et al. Neutrophils promote Alzheimer's disease–like pathology and cognitive decline via LFA-1 integrin. Nat Med 21, 880–886 (2015). https://doi.org/10.1038/nm.3913

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