Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of Aβ and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice

Abstract Vascular dysregulation and cholinergic basal forebrain degeneration are both early pathological events in the development of Alzheimer’s disease (AD). Acetylcholine contributes to localised arterial dilatation increased cerebral blood flow (CBF) during neurovascular coupling via activation endothelial nitric oxide synthase (eNOS). Decreased vascular reactivity is suggested contribute impaired clearance β-amyloid (Aβ) along intramural periarterial drainage (IPAD) pathways brain, leading amyloid angiopathy (CAA). However, possible relationship between loss innervation, vasoreactivity reduced Aβ from brain has not been previously investigated. In present study, intracerebroventricular administration mu-saporin resulted significant death neurons fibres medial septum, cortex hippocampus C57BL/6 mice. Arterial spin labelling MRI revealed a CBF response stimulation eNOS by Rho-kinase inhibitor fasudil hydrochloride denervated By contrast, remained responsive drug treatment, association with altered expression. Fasudil significantly IPAD control saporin-treated mice, while was only observed animals. Administration TetOAPPSweInd mouse model AD associated selective increase Aβ40-positive CAA. These findings support importance interrelationship innervation function aetiology and/or progression CAA suggest that combined eNOS/cholinergic therapies may improve efficiency removal reduce its deposition as