The COVID-19 pandemic is associated with neurological symptoms and complications including stroke. There is hypercoagulability associated with COVID-19 that is likely a "sepsis-induced coagulopathy" and may predispose to stroke. The SARS-CoV-2 virus binds to angiotensin-converting enzyme 2 (ACE2) present on brain endothelial and smooth muscle cells. ACE2 is a key part of the renin angiotensin system (RAS) and a counterbalance to angiotensin-converting enzyme 1 (ACE1) and angiotensin II. Angiotensin II is proinflammatory, is vasoconstrictive, and promotes organ damage. Depletion of ACE2 by SARS-CoV-2 may tip the balance in favor of the "harmful" ACE1/angiotensin II axis and promote tissue injury including stroke. There is a rationale to continue to treat with tissue plasminogen activator for COVID-19-related stroke and low molecular weight heparinoids may reduce thrombosis and mortality in sepsis-induced coagulopathy.

For many years, modulators of the renin angiotensin system (RAS) have been trusted by clinicians for the control of essential hypertension. It was recently demonstrated that these modulators have other pleiotropic properties independent of their hypotensive effects, such as enhancement of cognition. Within the brain, different components of the RAS have been extensively studied in the context of neuroprotection and cognition. Interestingly, a crosstalk between the RAS and other systems such as cholinergic, dopaminergic and adrenergic systems have been demonstrated. In this review, the preclinical and clinical evidence for the impact of RAS modulators on cognitive impairment of multiple etiologies will be discussed. In addition, the expression and function of different receptor subtypes within the RAS such as: Angiotensin II type I receptor (AT1R), Angiotensin II type II receptor (AT2R), Angiotensin IV receptor (AT4R), Mas receptor (MasR), and Mas-related-G protein-coupled receptor (MrgD), on different cell types within the brain will be presented. We aim to direct the attention of the scientific community to the plethora of evidence on the importance of the RAS on cognition and to the different disease conditions in which these agents can be beneficial.

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