The COVID-19 pandemic has revealed the devastating impact of the virus on global health. Beyond its initial classification as a respiratory illness, COVID-19 has demonstrated its ability to affect the central nervous system, resulting in a range of neurological disorders. A new hypothesis proposes that the cleavage of the SARS-CoV-2 spike protein by furin protease may play a significant role in the development of these neurological complications. This hypothesis offers valuable insights into the mechanisms by which SARS-CoV-2 exacerbates neurological damage, leading to cognitive impairments and neurodegenerative diseases.
Research indicates that more than 35% of COVID-19 cases are associated with central nervous system issues, varying from mild symptoms to severe complications like cognitive impairments, stroke, and encephalopathy. Studies have also observed shrinkage of the hippocampus, reduction in brain size, and neurodegeneration following SARS-CoV-2 infection, emphasizing the need for a comprehensive understanding of the virus’s impact on the central nervous system.
The renin-angiotensin system (RAS), which plays a crucial role in regulating blood pressure and fluid balance, is also integral to neurological health. SARS-CoV-2 enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2), a key component of the RAS. When the virus’s spike protein interacts with ACE2, it leads to the downregulation of ACE2, resulting in elevated levels of angiotensin II (Ang II), a vasoconstrictor associated with neurological disorders. Increased Ang II levels contribute to neuroinflammation, oxidative stress, and reduced cerebral blood flow, potentially leading to neurological complications.
Alternative axes of the RAS, such as the ACE2/Ang 1-7/Mas receptor and ACE2/Ang 1-7/AT2 receptor pathways, have been found to offer protective effects against neurodegenerative diseases. These pathways reduce inflammation, oxidative stress, and promote vasodilation and neuroprotection. Inhibiting the RAS has shown promise in reducing the risk of developing neurological disorders.
The spike protein of SARS-CoV-2 plays a critical role in its interaction with ACE2. Animal studies have demonstrated the impact of the spike protein on ACE2 expression and lung injury. Evidence also suggests that SARS-CoV-2 affects ACE2 mRNA expression, further reducing ACE2 levels. Immunohistochemical evaluations of COVID-19 patients have shown reduced ACE2 protein expression, even in patients with Alzheimer’s disease.
The hypothesis proposes that the cleavage of the spike protein by furin protease may amplify its effects on ACE2 downregulation, contributing to the neurological complications observed in COVID-19 patients. Furin protease cleaves the spike protein, releasing fragments that can target ACE2 receptors. This amplification process could significantly decrease ACE2 expression and increase Ang II levels. If substantiated, this hypothesis could have significant implications for COVID-19 patients and the development of vaccines.
Understanding the mechanisms through which SARS-CoV-2 impacts the central nervous system is essential for the development of effective treatment strategies and the prevention of neurological complications. Further research and clinical studies are necessary to validate this hypothesis and explore potential therapeutic interventions using furin inhibitors.