Signs of Endothelial Inflammation in Human Neurodegeneration

Researchers here provide evidence from human blood samples that supports a role for vascular inflammation in age-related neurodegeneration. It is becoming clear that a great deal of tissue-specific information can be harvested from extracellular vesicles present in the bloodstream, if their contents were only better mapped and understood. The research community is still quite early in the process of establishing the necessary knowledge, but proof of concept demonstrations such as the study noted here are now emerging on a regular basis.

Cerebrovascular disease and the associated blood-brain barrier (BBB) dysfunction are intimately associated with immune activation and among the most common age-associated, inflammation-mediated, degenerative brain changes. Vascular pathways are emerging as an important contributor to neurodegenerative disorders. Importantly, immuno-vascular dysregulation can cause pathology in early disease states, prior to frank brain degeneration and clinical manifestations such as mild cognitive impairment. More recently, molecular pathways are emerging to suggest a feed-forward degenerative-inflammatory phenomenon between endothelial cells, innate immune activation, and degenerative myelin debris. Therefore, identification of molecular biomarkers of immuno-vascular disease in preclinical states has important therapeutic implications for extension of health span, treatment of vascular cognitive impairment.

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.


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