High blood pressure and cyclic stretch after cerebral amyloid deposition and endothelial function
thesisposted on 2022-03-28, 13:46 authored by Sumudu V. S. Gangoda
Background: Amyloid β (Aβ) deposition is a hallmark of Alzheimer’s disease (AD). Increased pulsatility, endothelial dysfunction (ED) and inflammation, indicators of vascular stiffness, are associated with AD. Additionally, vascular stiffness is linked to hypertension, a risk factor for AD. Aim: This study aimed to determine effects of high blood pressure (BP) on cerebral Aβ deposition in rodent models, spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) and investigate effects of cyclic stretch (CS) on expression of amyloid precursor protein (APP), endothelial nitric oxide synthase (eNOS) and intercellular cell adhesion molecule-1 (ICAM-1) in human cerebral microvascular endothelial cells (hCMEC). Methods: Hippocampal (HC) and frontal cortex (FC) regions of SHR and WKY rats were analysed using western blotting to determine effect of BP on cerebral Aβ deposition. hCMEC were subjected to 5%, 10% or 20 % CS compared to control (0% CS) to evaluate pulsatility, ED and inflammation using western blotting and/or RTqPCR. Results: Aβ oligomerisation increased in SHR compared to WKY in HC (P<0.01) and FC (P<0.001). APP mRNA expression increased at 5%, decreased at 20% CS; eNOS decreased at both (P<0.0001). APP and ICAM-1 protein expression dose-dependently increased at 5% and 10% CS (P<0.01) and decreased at 20% CS. eNOS protein levels decreased at all CS (P<0.0001). Conclusions: Results suggest that high BP and CS respectively alter the processing and expression of cerebral APP. Prolonged CS may induce ED by increasing ICAM-1, thereby mitigating eNOS expression. Findings mechanistically support the association of elevated pulsatility and arterial stiffness with AD.