Vessel-associated microglia are differentially activated and distributed in relation to systemic infection and Alzheimer's disease.

Vessel-associated microglia (VAM) are an integral part of the neurovascular unit and have recently been implicated in the pathophysiology of cerebrovascular injury and blood-brain barrier (BBB) leakiness in Alzheimer's disease (AD). In this neuropathological study, we explored the hypothesis that the distribution and activation of VAM are altered in AD in the presence of systemic infection, associated with cerebrovascular dysfunction. We studied VAM density in the temporal cortex and underlying white matter from AD and age-matched controls with and without terminal systemic infection (SI) (n = 15 per group). The area of VAM labelled with microglial markers (Iba1, HLA-DR, CD68) was quantified in proximity to CD31-labelled microvessels within three predefined regions: contact VAM, proximity <15 μm, and parenchymal >15 μm. The relationships between VAM and previously measured brain cytokine levels and biochemical markers of cerebral perfusion (MAG:PLP1, endothelin-1) and BBB leakiness (VEGF-A and fibrinogen), were explored in a subset of cases. Compared to controls, the relative area of Iba1+ VAM was higher in SI and in AD. The area of HLA-DR+ VAM was higher in AD only. The area of Iba1+ VAM that expressed CD68, a marker of phagocytosis, was higher in both AD and AD + SI. Iba1+ and HLA-DR+ VAM correlated inversely with anti-inflammatory cytokines (IL-10, IL-23) in AD and positively with pro-inflammatory cytokines (IL-6, IL-23, GM-CSF, IL-17) in AD + SI. Iba1+ VAM density correlated positively with endothelin-1, VEGF-A and fibrinogen in controls. HLA-DR+ VAM density correlated positively with Aβ(1-42) in both controls and AD, and inversely with PDGFRβ and VCAM-1 in AD. Our data reveal the distribution of VAM is elevated in AD, and altered in the presence of systemic infection, which together are likely to be independent and synergistic contributors to cerebrovascular dysfunction in AD.