Elevated complement mediator levels in endothelial-derived plasma exosomes implicate endothelial innate inflammation in diminished brain function of aging humans

Abstract

We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70–82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling. EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated significant associations with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components. These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.

Overview of extracellular vesicle characterization techniques and introduction to combined reflectance and fluorescence confocal microscopy to distinguish extracellular vesicle subpopulations

“…For example, brain endothelium-derived EVs isolated from the plasma of patients with small cerebrovascular disease were found to carry elevated levels of complement mediators compared with controls, indicative of an inflammatory phenotype in brain endothelial cells which could contribute to cerebral white matter injury. 107 However, despite these advances, the small size and heterogeneous nature of EVs mean that their characterization remains a challenging task. Classical techniques such as Western blotting and ELISA can be helpful for evaluation of their content and surface markers, and electron microscopy is still the gold-standard for their morphologic evaluation, but these approaches either require large amounts of sample, lengthy procedures, specialist equipment, or do not provide information about the molecular heterogeneity in an EV preparation.…”

Zerebrale Mikroangiopathie: Fortschritte im Verständnis der Pathophysiologie

“…Bei kognitiv normalen älteren Menschen mit und ohne Nachweis von WMH in der Bildgebung des Gehirns, konnte eine Assoziation z. B. von endothelialen EVs im Blut mit zerebralen mikroangiopathischen Veränderungen/WMH im MRT gezeigt werden [42].…”

Mechanisms and Biomarker Potential of Extracellular Vesicles in Stroke

“…EVs have also been shown to demonstrate potential as indicators of cerebral small vessel disease, suggesting a utility for them in the detection of ongoing endothelial dysfunction occurring in the post-stroke scenario [ 99 ]. Considering the damage occurring to the BBB following AIS, it is probable that EVs derived from endothelial cells provide unique insight into BBB integrity.…”