Nitric oxide-mediated changes in glymphatic and CSF systems in aging and Alzheimer's disease

ABSTRACTSARS-CoV-2 contact with the organism starts with binding to its key receptor ACE2 which is highlyexpressed in the ciliated cells of the tracheal, bronchial, and nasal mucociliary epithelium. After binding,the virus inhibits the cilia beating in the airways and suppresses mucociliary transport, the first line ofdefense against invading microorganisms. Thus, augmenting the ciliary function may prevent the viralinfection at the very first steps or help fight the further propagation of the virus. ACE2 is also expressedin selected brain cells, underlying the neurological effects of SARS-CoV-2.The main objective of this supplement is to rapidly build a screening system, to identify drugs that canbe immediately applied for COVID-19 therapy, and to use the gained knowledge for expanding thescreen to a broader range of candidate compounds.In our NIA supported grant we discovered the critical role of the nNOS-NO-cGC-cGMP signalingpathway for ciliary activity in the brain and the airways. Here we describe our plans of targeting thispathway with clinically-approved drugs in order to augment cilia activity and airways clearance. Thisproject can be later extended to build a sensitive and powerful drug screen for anti-COVID-19 therapy.In our first Specific Aim we will develop a comprehensive computational toolbox and use it todetermine the key parameters (a signature) of the cilia activity in the airways' and brain ciliated cellsfrom humans and humanized mouse model. In the second Specific Aim, we will apply our setup todetermine the signature of the cilia response to S1, the main cell binding ligand of SARS-CoV-2, and toS1-expressing pseudotyped VSV-S1 virus. Finally, in our third Specific Aim we will examine anti-SARS-CoV-2 drugs currently used in clinic and clinically-approved compounds that activate the NO-cGMP pathway, as well as their combination to determine if such treatments can rescue the S1-affectedcilia activity in the airways and brain preparations. In the same set of experiments we will examine theresponse of preparations from animals of different age, which may contribute to the profound old age-bias of COVID-19. We emphasize that our selection of drugs to be tested is limited to thetherapeutically-approved compounds, thus enabling rapid translation of our findings into clinicalpractice.