Vascular endothelial‐cadherin as a marker of endothelial injury in preclinical Alzheimer disease

Abstract

Objective Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial‐cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. Methods Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University‐ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p‐tau181, Aβ42/Aβ40, neurofilament light‐chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid‐PET) (n = 534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. Results CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T±N±; n = 558) or those with amyloid and tau pathologies (A+T+N±; n = 259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid‐PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Aβ42/Aβ40, p‐tau181, and global amyloid burden with cognitive outcomes in preclinical AD. Interpretation Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages.

Circulating exosomes from Alzheimer’s disease suppress VE-cadherin expression and induce barrier dysfunction in recipient brain microvascular endothelial cell

“…Microvasculature injury is a common observation in most AD brains, even in preclinical stages 109,110 . While VE-cad in cerebrospinal fluid (CSF) was reported as a biomarker of endothelial injury in preclinical AD 33 , there is a lack of information on the functional role of AJs during BBB dysfunction in AD. BBB properties are primarily determined by the AJs and TJs 26,111 , with BMECs forming extremely tight TJs that are distinct from endothelial or epithelial TJs elsewhere, which have fenestrations and high rate of pinocytosis 112,113 .…”

“…Studies on developmental stage suggest a high level of interdependency between AJs and TJs during the formation of cell-cell contacts between ECs 114,120-122 . Interestingly, the expression level of VE-cad in CSF is increased in preclinical AD and correlates with cognitive impairment 33 , but underlying mechanisms remain unknown. We noted that in AD brains, microvascular endothelial AJ protein VE-cad was downregulated.…”

“…BMEC activation or injury is an early and prevalent event in AD [15][16][17][18]33,37,38,[86][87][88][89][90][91] . To assess the potential effects of circulating exosomes on BMECs, we isolated exosomes from 0.2 µm-filtered sera of 5 cases of AD with clinical dementia rating (CDR) scores of 3 compared with 5 cases age-and sex-matched cognitively normal controls with CDR 0 (see Table ), using size-exclusion chromatography (SEC) that was documented with improved integrity, yield, and no aggregation compared with other methods 53,[92][93][94][95] .…”

“…Loss of some, or most, of the BBB properties is a documented component of the progression and pathology of AD 15,[31][32][33][34] . BBB dysfunction is primarily caused by reduced or disorganized TJ/AJ proteins or enhanced transendothelial bulk flow of specific molecules by transcytosis 1,2,35 .…”

“…More than 20 independent postmortem human studies have documented BBB breakdown in AD, revealing BMEC degeneration, TJ disruption, microhemorrhages, and hemosiderin deposits 39 . Although VE-cad in cerebrospinal fluid (CSF) has been reported as a biomarker of endothelial injury in preclinical AD 33 , there is a lack of information regarding the functional role of AJs during BBB dysfunction in AD.…”