Neutrophil-vascular interactions drive myeloperoxidase accumulation in the brain in Alzheimer's disease.
Alzheimer’s disease
Blood–brain barrier
Myeloperoxidase
Neutrophil
Neutrophil extracellular trap
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
24 03 2022
24 03 2022
Historique:
received:
09
02
2022
accepted:
11
03
2022
entrez:
25
3
2022
pubmed:
26
3
2022
medline:
3
5
2022
Statut:
epublish
Résumé
Neutrophil accumulation is a well-established feature of Alzheimer's disease (AD) and has been linked to cognitive impairment by modulating disease-relevant neuroinflammatory and vascular pathways. Neutrophils express high levels of the oxidant-generating enzyme myeloperoxidase (MPO), however there has been controversy regarding the cellular source and localisation of MPO in the AD brain. We used immunostaining and immunoassays to quantify the accumulation of neutrophils in human AD tissue microarrays and in the brains of APP/PS1 mice. We also used multiplexed immunolabelling to define the presence of NETs in AD. There was an increase in neutrophils in AD brains as well as in the murine APP/PS1 model of AD. Indeed, MPO expression was almost exclusively confined to S100A8-positive neutrophils in both human AD and murine APP/PS1 brains. The vascular localisation of neutrophils in both human AD and mouse models of AD was striking and driven by enhanced neutrophil adhesion to small vessels. We also observed rare infiltrating neutrophils and deposits of MPO around plaques. Citrullinated histone H3, a marker of neutrophil extracellular traps (NETs), was also detected in human AD cases at these sites, indicating the presence of extracellular MPO in the vasculature. Finally, there was a reduction in the endothelial glycocalyx in AD that may be responsible for non-productive neutrophil adhesion to the vasculature. Our report indicates that vascular changes may drive neutrophil adhesion and NETosis, and that neutrophil-derived MPO may lead to vascular oxidative stress and be a relevant therapeutic target in AD.
Identifiants
pubmed: 35331340
doi: 10.1186/s40478-022-01347-2
pii: 10.1186/s40478-022-01347-2
pmc: PMC8944147
doi:
Substances chimiques
MPO protein, human
EC 1.11.1.7
Peroxidase
EC 1.11.1.7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
38Informations de copyright
© 2022. The Author(s).
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