Abstract
The amyloid-β precursor protein (APP) is a ubiquitous membrane protein often associated with Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Despite its role in the development of the pathogenesis, APP exerts several physiological roles that have been mainly investigated in neuronal tissue. To date, the role of APP in vasculature and endothelial cells has not been fully elucidated. In this study, we used molecular and proteomic approaches to identify and investigate major cellular targets of APP down-regulation in endothelial cells. We found that APP is necessary for endothelial cells proliferation, migration and adhesion. The loss of APP alters focal adhesion stability and cell–cell junctions’ expression. Moreover, APP is necessary to mediate endothelial response to the VEGF-A growth factor. Finally, we document that APP propagates exogenous stimuli and mediates cellular response in endothelial cells by modulating the Scr/FAK signaling pathway. Thus, the intact expression and processing of APP is required for normal endothelial function. The identification of molecular mechanisms responsible for vasoprotective properties of endothelial APP may have an impact on clinical efforts to preserve and protect healthy vasculature in patients at risk of the development of cerebrovascular disease and dementia including AD and CAA.
Highlights
The amyloid-β precursor protein (APP) is a ubiquitous type-1 integral membrane protein that plays an important role in neurovascular degeneration [1]
We observed a significant increase of cellular permeability in human umbilical vein ECs (HUVECs) lacking APP under basal conditions (CTRL)
While the pathological outcome of APP dysregulation is mainly associated to its overexpression, While the pathological outcome of APP dysregulation is mainly associated to its recent studies showed that APP expression levels tend to decrease with age [59,60], and APP-knockout overexpression, recent studies showed that APP expression levels tend to decrease with age [59,60], mice show age-dependent cognitive deficit and impaired locomotor activity [61,62]
Summary
The amyloid-β precursor protein (APP) is a ubiquitous type-1 integral membrane protein that plays an important role in neurovascular degeneration [1]. Full-length APP functions as a membrane cell adhesion molecule in the developing nervous system by binding to several extracellular matrix components (HSPGs, reelin, laminin and F-spondin) and interacting with numerous adaptor proteins and other cell adhesion molecules (integrins, neural cell adhesion molecules) [8,9,10,11,12,13]. APP presents a conserved YENPTY cytoplasmatic domain similar to non-receptor tyrosine kinases; this motif interacts with scaffold proteins associated with the dynamics of the cytoskeleton and has been shown to regulate gene transcription. These features indicate that APP is involved in propagating extracellular responses [14]
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