Abstract WMP23: Tobacco Cigarette Smoking Causes Cognitive Impairment Through Cerebrovascular Oxidative Damage

Abstract

Introduction: Tobacco cigarette smoking (TCS) has been established as a risk factor for cardiovascular disease. Recent epidemiological studies have identified an association between TCS and cognitive impairment. However, the underlying mechanisms are yet to be established. We hypothesize that chronic TCS induces systemic and cerebrovascular oxidative stress that leads to cognitive impairment. Methods: Male C57BL6 mice were exposed to cigarette smoke or air (two hours per day, five days per week) for up to 60 weeks, n =10/group. The vascular reactivity of the carotid artery (CA) was assessed using a wire myograph. The CA blood flow was measured by Doppler ultrasonography. Dihydroethidium and diaminofluorescein were used to measure superoxide and nitric oxide. Endothelial nitric oxide synthase (eNOS), tight junction proteins (occludin and caudine-5), β-amyloid, and phosphorylated Tau were measured by immunoblotting and immunofluorescence microscopy. We assessed the cognitive function using Barnes Maze and fear conditioning testing. Results: Vascular endothelial dysfunction occurred in the CA after 16 weeks of TCS exposure, followed by a 23% reduction in CA blood flow (P=0.0006). Superoxide was significantly elevated in the CA and subsequently in the brain of TCS-exposed mice by 181% (P<0.0001), compared to air-exposed mice. Reduction in eNOS and tight junction proteins were observed in the cerebrovascular endothelial cells. At 60 weeks of exposure, the brain of TCS-exposed mice showed higher levels of β-amyloid and phosphorylated-tau (352% and 260%, P=0.0032 and P<0.0001, respectively), compared to air-exposed mice. At this time, TCS-exposed mice exhibited impaired spatial learning and memory. Conclusions: TCS causes progressive systemic and cerebrovascular oxidative damage, leading to cognitive impairment. Targeting vascular oxidative stress is a potential strategy to mitigate cognitive function impairment.