Neutrophil-derived microvesicle-induced blood brain barrier dysfunction and white matter lesion formation in the ageing brain

Age-associated white matter lesions (WML), an independent risk factor for dementia, are histologically characterised by endothelial cell activation, blood brain barrier dysfunction, and microglial activation. Systemic inflammation can interact with brain endothelium and exacerbate neurodegenerative processes, leading to accelerated progression of dementia. The mechanisms by which systemic inflammation affects WM pathology and cognitive decline in the ageing population are, as yet, unknown. Neutrophils, first responder cells of the innate immune system, are significantly higher in dementia patients and are associated with cognitive decline in Alzheimer’s disease (AD) patients who are hospitalised due to infection. Activated neutrophils produce neutrophil-derived microvesicles (NMVs) which modulate systemic endothelial function but, to date, the effect of NMVs on brain endothelial cells is unknown. We hypothesise that during an inflammatory event, NMVs interact with brain microvascular endothelial cells leading to dysfunction of the blood brain barrier (BBB), microglial activation, WML formation and cognitive decline.