Abstract: Application is submitted here in response to PA-17-296. The efficient clearance of waste metabolites is compromised in the brain due to lack of lymphatic system and cerebrospinal fluid (CSF) is not able to clear large size waste metabolites. Recent discovery of glymphatic system is able to transport small size water-soluble waste metabolites directly to perivenous space by aquaporin-4 water channels of the astrocyte end-feet. Thus, unravelling the mechanisms of clearing large size waste metabolites in the CNS become significant for therapeutic prevention of neurological diseases associated with entangled proteins. Here, we propose to address the clearance mechanisms of fluorescent labeled ?-amyloid protein from interstitial fluid to perivascular space or from CSF subarachnoid into perivenous drainage through perivascular clearance path. We propose that this dynamic perivascular-perivenous drainage path is significantly promoted by low dose alcohol (ethanol), and not by high dose or chronic alcohol use. Our working hypothesis is that activation of cerebral arterial endothelial specific nitric oxide synthase (eNOS) by alcohol (5 mM) led to generation of a potent vasodilator nitric oxide, which mediates the interactive reactivity of endothelial-smooth muscle cells and subsequent inter-convective movement of waste metabolites towards perivascular space. We will address the hypothesis, first, by establishing the existence of perivascular clearance path and how alcohol promotes this drainage path, and second by evaluating the underlying molecular mechanisms of perivascular clearance by alcohol-elicited endothelial NO that promotes endothelial- smooth muscle cells dilative reactivity and subsequent waste metabolites clearance. Knowledge gained from this project is expected to bear a significant impact for possible prevention of neurological disorders such as cerebral amyloid angiopathy and Alzheimer's disease.