Endothelial-derived exosomes demonstrate a link between endothelial innate inflammation and brain dysfunction and injury in aging

Abstract

We test the hypothesis that endothelial cells take on an inflammatory phenotype in functionally intact human subjects with radiographic evidence of white matter injury. Markers within all three complement effector pathways and regulatory proteins were quantified from endothelial-derived exosomes (EDE) of subjects (age 70-82) with (n=11) and without (n=16) evidence of white matter hyperintensity on MRI. Group differences and associations with systemic 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 several factors demonstrated significant associations with cognitive slowing and systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Systemic inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several factors.These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter injury, cognition, and brain degeneration in functionally normal older individuals, and form the basis for future biomarker development in early or preclinical stages of vascular cognitive impairment and dementia.

Immune cell counts in cerebrospinal fluid predict cognitive function in aging and neurodegenerative disease

“…Consistent with this, mouse models show that inflammation has a selective impact on executive functions while sparing memory 19 . Additionally, this finding is supported by observations from other neurological diseases where executive dysfunction is prominent, including both primary autoimmune conditions such as multiple sclerosis and autoimmune encephalitis, as well as other neurodegenerative disorders such as vascular‐related cognitive impairment 6,10,12,47,48 . Many studies have similarly found an association with peripheral markers of inflammation and executive function broadly as well as verbal fluency specifically, although none have reported this finding within the CSF 49–53 .…”

“…19 Additionally, this finding is supported by observations from other neurological diseases where executive dysfunction is prominent, including both primary autoimmune conditions such as multiple sclerosis and autoimmune encephalitis, as well as other neurodegenerative disorders such as vascular-related cognitive impairment. 6,10,12,47,48 Many studies have similarly found an association with peripheral markers of inflammation and executive function broadly as well as verbal fluency specifically, although none have reported this finding within the CSF. [49][50][51][52][53] Moreover, it has also been demonstrated that immune activation alters brain connectivity specifically in the executive network while sparing the default mode network associated with memory as well as the salience network associated with emotional regulation.…”

“…Emerging studies show that changes in the immune system are inherent to the pathophysiology of aging. [2][3][4] Increasingly, the immune system is implicated in the pathogenesis of neurodegenerative diseases, [2][3][4][5][6][7] and this involvement may be one of the ways aging predisposes the brain to neurodegeneration. In the blood, declines in serum lymphocyte numbers and changes in cytokine levels are seen with age.…”

Inflammation and the Link to Vascular Brain Health: Timing Is Brain

“…Complement cascades play an important role in thrombosis and are increased in exosomes released from endothelial cells in individuals with chronic cerebrovascular disease and may be associated with COVID-19-related thrombosis. 55,72 In acute stroke injury, blocking the alternative complement pathway through CR2 (complement receptor 2) inhibition can reduce the robust inflammatory infiltrate into ischemic brain tissue while preserving the ability for opsonins in the classical complement pathway to modulate synaptic pruning and debris clearance. 73 In chronic cerebrovascular disease, steady, low-level inhibition of particular complement cascades could reduce microvascular thrombosis, blood-brain barrier leakage, or both thereby reducing the progression of white matter injury.…”

Pathophysiologic mechanisms of cerebral endotheliopathy and stroke due to Sars-CoV-2

“…Complement activation is known to play a significant role in human and experimental models of stroke 24 as well as cerebral small vessel disease. 25 Ischemia-induced exposure of neo-epitopes on cerebral endothelium can also trigger complement activation. 26 MASP-2 knockout mice exposed to transient middle cerebral artery occlusions have reduced stroke volumes, improved neurologic outcomes, and reduced C3 deposition in the cortex.…”