Abstract
Amyloid β (Aβ) deposition is a hallmark of Alzheimer’s disease (AD). Vascular modifications, including altered brain endothelial cell function and structural viability of the blood-brain barrier due to vascular pulsatility, are implicated in AD pathology. Pulsatility of phenomena in the cerebral vasculature are often not considered in in vitro models of the blood-brain barrier. We demonstrate, for the first time, that pulsatile stretch of brain vascular endothelial cells modulates amyloid precursor protein (APP) expression and the APP processing enzyme, β-secretase 1, eventuating increased-Aβ generation and secretion. Concurrent modulation of intercellular adhesion molecule 1 and endothelial nitric oxide synthase (eNOS) signaling (expression and phosphorylation of eNOS) in response to pulsatile stretch indicates parallel activation of endothelial inflammatory pathways. These findings mechanistically support vascular pulsatility contributing towards cerebral Aβ levels.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia
Vascular stiffness is related to endothelial dysfunction where nitric oxide (NO)-mediated-endothelium-dependent vasodilation, which is facilitated by the enzyme, endothelial NO synthase, is diminished
After HCMECs were stretched for 18 hours at 0%, 5%, 10% or 15% stretch magnitudes, the qPCR analysis of amyloid precursor protein (APP) mRNA expression was significantly higher than the static control (105 ± 17%) at 10% (184 ± 19%, P < 0.05) and 15% (243 ± 17%, P < 0.001; Fig. 1a) stretch
Summary
Alzheimer’s disease (AD) is the most common form of dementia. Post-mortem brain tissue examination reveals amyloid plaques, which are considered to play an important role in the pathophysiology of AD1. Higher pulsatility index and pulse pressure, indicative of increased large artery stiffness and reduced vessel compliance, are associated with AD, lower memory scores, increased amyloid burden and cerebral microvascular damage[3,4]. Elevated expression and localisation of inflammatory markers such as intercellular cell adhesion molecule-1 (ICAM-1) surrounding AD-plaques have been demonstrated[5]. Increased pulse pressure, vascular stiffness and hypertension could impose increased mechanical stretch on microvessel walls. The consequence of this chronic stress placed upon cerebral microvascular ECs is currently unknown
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