Vascular primary cilia in the pathogenesis of hypertension and Alzheimer's Disease

Abstract

AbstractBackgroundPrimary cilia are microtubule‐based organelles, extending from the surface of cells to sense extracellular signaling cues. We demonstrated that the inability of endothelial cilia to sense and transmit fluid‐shear stress can lead to nitric oxide (NO) deficiency and cause vascular HTN. HTN can cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment, contributing to the progression of AD. It is well documented that decreased biosynthesis of NO contributes to cerebral amyloid angiopathy in AD patients through increased deposition of Aβ. Disruption of the cholinergic neurotransmitter pathway, which is important for cognition, memory and learning abilities has been reported in AD patients. However, the connection between cilia and mAChR signaling in the brain has never been investigated. We propose a bold idea to look at the pathophysiological roles of cerebrovascular ciliary receptors in BP and AD.MethodImmunofluorescence of human brain endothelial cells (HBECs) were employed to study AChM3R localization and its downstream effectors. Cilia length and function (eNOS activation) studies were carried out to examine if mAChRs activation would enhance cilia structure and function. siRNA‐mediated knockdown of Tulp‐3 was performed to block AChM3R trafficking to primary cilia and study its activity. HBECs were exposed to synthetic Aβ to study their effect on cilia structure and ciliogenesis. Vascular‐specific cilia and AChM3R knockout mice were generated to study blood pressure and AD manifestations.ResultWe discovered that AChM3R, PIP2, and eNOS localize to primary cilia. mAChR‐specific activation (CDD‐0102A) increases cilia length in HBECs and cilia formation in cilialess Tg737 cells and was also associated with an increase in eNOS activity. Exposure to 2.5 μM human Aβ42 resulted in significant reduction in primary cilia length and ciliation percentage. RNAi‐mediated knockdown of Tulp3 caused a significant decrease in AChM3R trafficking to the cilia, associated with altered activity, suggesting that ciliary AChM3R localization is important for its activity. Vascular‐specific AChM3R and Tg737 KO mice developed high BP. Studies to examine cognitive function in our animal models are underway.ConclusionPrimary cilia play an important sensory role by hosting proteins and signaling molecules important for the regulation of blood pressure and cognitive function.