Effect of Covid-19 engagement of ACE2 on brain health and pathology

AbstractThere are mechanisms in the brain that regulate interactions between neurons and microglialcells and promote homeostasis. These are perturbed in several diseases includingneuropsychiatric lupus, NPSLE, studied in this PPG, and following sepsis. Many conditions ofneuroinflammation are characterized by microglial activation, and, as a consequence of thisactivation, by neuronal dendritic pruning and an impaired blood brain barrier. Interestingly, apathway regulating homeostasis in the brain and dysregulated by neuroinflammation is therenin-angiotensin system. Angiotensin II is generated by angiotensin converting enzyme, ACE,and binds to a receptor AT-1 to enhance inflammation. ACE inhibitors or angiotensin receptorblockers, ARBs, can improve neuroinflammation by either decreasing production or neutralizingangiotensin II. In this pathway, ACE2, a membrane-bound protease, also functions to destroyangiotensin and to generate a small angiotensin peptide, ang1-7, that is anti-inflammatory.ACE2 is the cellular receptor for Covid-19, and binds the viral spike protein, S, more specifically,the receptor binding domain, RBD. This study will examine the binding of S and RBD to normalmouse brain and to mouse brain mimicking NPSLE or sepsis survival. We will further studywhether engagement by S or RBD alters the functional state of neurons, microglia and brainendothelial cells. Finally, we ask whether the use of ACE inhibitors or ARBs alters S or RBDbinding, and whether S or RBD impair the efficacy of these medications in halting or reversingthe neurodegenerative process in NPSLE and in sepsis survivors. This study cannot beperformed in humans, but it has important translational implications.