Neutrophil-vascular interactions drive myeloperoxidase accumulation in the brain in Alzheimer’s disease

Abstract

Introduction 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. Materials and methods 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. Results 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. Conclusion 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.

The role of neutrophils in the dysfunction of central nervous system barriers

“…Moreover, MPO + cells (probably neutrophils) were increased in the brain in subjects with AD and Parkinson’s disease (PD) ( Zenaro et al, 2015 ; Gellhaar et al, 2017 ), thus supporting a role for this enzyme in neurodegeneration. Importantly, recent studies by Smyth et al have shown that MPO staining is mainly associated with infiltrating neutrophils in the AD brain, further providing evidence of a role for neutrophil-derived inflammatory factors in BBB dysfunction ( Smyth et al, 2022 ).…”

Non-Canonical Functions of Myeloperoxidase in Immune Regulation, Tissue Inflammation and Cancer

“…MPO is a common inflammatory marker, and elevated MPO levels are observed in many pathological conditions, including inflammatory bowel disease (IBD) [ 45 , 57 , 58 , 59 ], cardiovascular disease [ 60 , 61 , 62 , 63 ], obesity [ 43 , 64 , 65 ], liver disease [ 66 , 67 ], arthritis [ 68 ], multiple sclerosis [ 69 , 70 ], Alzheimer’s disease [ 71 ], stroke [ 72 ] and cancer [ 73 , 74 ] ( Table 1 ). MPO levels are elevated in IBD, and MPO inhibition in animal models of colitis is protective [ 58 , 75 , 76 ].…”

Research Progress of Targeting Neuro-Immune Inflammation in the Treatment of Alzheimer's Disease

“…Neutrophils release inflammatory mediators (such as MIF, IL2, and MPO) that promote the progression of AD neuroinflammation [33,34].…”

“…and the extracellular enzyme myeloperoxidase (MPO) is deposited in the blood vessels. These vascular changes drive neutrophil adhesion and neutrophil extracellular traps (NETs), ultimately leading to oxidative stress and cognitive impairment [34].…”