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

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ABSTRACT SARS-CoV-2 contact with the organism starts with binding to its key receptor ACE2 which is highly expressed 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 of defense against invading microorganisms. Thus, augmenting the ciliary function may prevent the viral infection at the very first steps or help fight the further propagation of the virus. ACE2 is also expressed in 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 can be immediately applied for COVID-19 therapy, and to use the gained knowledge for expanding the screen to a broader range of candidate compounds. In our NIA supported grant we discovered the critical role of the nNOS-NO-cGC-cGMP signaling pathway for ciliary activity in the brain and the airways. Here we describe our plans of targeting this pathway with clinically-approved drugs in order to augment cilia activity and airways clearance. This project 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 to determine the key parameters (a signature) of the cilia activity in the airways’ and brain ciliated cells from humans and humanized mouse model. In the second Specific Aim, we will apply our setup to determine the signature of the cilia response to S1, the main cell binding ligand of SARS-CoV-2, and to S1-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-affected cilia activity in the airways and brain preparations. In the same set of experiments we will examine the response 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 the therapeutically-approved compounds, thus enabling rapid translation of our findings into clinical practice.