Alteration of Vascular Endothelial Cadherin in Alzheimer’s Disease Patient and Mouse Model

Abstract

Alzheimer's disease (AD) is characterized by amyloid plaques and pathologic cerebrovascular remodeling. Cerebrovascular abnormalities may contribute to the pathology of AD, but the molecular mechanisms are not fully understood. In this study, we evaluated blood-brain barrier (BBB) disruption and the role of VE-cadherin in the progression of amyloid pathology. Here, we determined that levels of VE-cadherin are decreased in brain vessels of AD patients and mouse model of AD. In vitro experiments showed that the disappearance of VE-cadherin by betaamyloid at the endothelial cell surface was due to cleavage of VE-cadherin. VE-cadherin cleavage was inhibited by a γ-secretase and ADAM10 inhibitor. The disappearance of VE-cadherin in brain vessels was also seen in amyloid precursor protein transgenic mice. In the postmortem brain of individuals with AD, furthermore, levels of VE-cadherin were significantly reduced in vessels. Dementia patients showed a distinct blood biochemical profile characterized by high soluble VE-cadherin (sVEC). There was a strong association between plasma sVEC (adjusted odds ratio = 3.41, P < 0.001) and dementia. These results suggest that measurements of plasma VE-cadherin could have the potential for predicting the risk of progressive AD.

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

“…VEC (Cadherin‐5; CD144) is an abundant calcium‐dependent endothelium‐specific adhesion molecule that is a key component of endothelial tight junctions 21 and is involved in regulating endothelial monolayer permeability, angiogenesis, and leukocyte adhesion 21–23 . Altered brain VEC expression levels have been reported in animal models of AD 71 . Consistent with these reports, we here demonstrate that brain VEC expression levels are reduced in human AD brains and are associated with increased CSF VEC levels, likely reflecting the release of abundant endothelial proteins into the extracellular space due to endothelial cell injury.…”

Understanding ultrasound-mediated blood-brain barrier opening as a potential non-invasive therapeutic approach for Alzheimer’s disease

“…however, the opposite has also been reported [235]. Changes to claudin-5 and other TJPs in AD may be driven by Aβ [229,234,236]. We observed that AD-iBECs with a PSEN1 mutation inherently expressed higher levels of some TJPs compared to healthy iBECs.…”

“…Reduced VE-cadherin expression in an AD mouse model and in post mortem tissue of AD patients has been reported [229]. VE-cadherin is a key component of adherens junctions, and its loss increases vascular permeability [213,229].…”

“…Reduced VE-cadherin expression in an AD mouse model and in post mortem tissue of AD patients has been reported [229]. VE-cadherin is a key component of adherens junctions, and its loss increases vascular permeability [213,229]. In contrast, claudin-3 and claudin-5 are both key barrier-forming claudins [230]; thus, their reduced expression in AD could cause the observed reduction in BBB integrity.…”

Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

“…One study shows that the TJ expression level is negatively correlated with the insoluble Aβ level in the cortex of human post-mortem tissues [ 76 ]. In addition, VE-cadherin, a component of endothelial adherens junctions that is important for maintaining vascular integrity, was also reported to decrease in AD patients and mouse brains [ 77 ].…”