The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer's disease (AD), the major form of dementia, beta-amyloid (A beta) levels in the blood are increased; however, the impact of elevated A beta levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that A beta(1-42), but not A beta(1-40), bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of A beta(1-42). Furthermore, A beta(1-42) strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of A beta(1-42) show that the clearance of A beta(1-42) in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-A beta antibody. In conclusion, these findings suggest that the binding of A beta(1-42) to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of A beta(1-42) in the blood is beneficial to the fight against COVID-19 and AD.

Automated summary

Elderly individuals with dementia, particularly Alzheimer's disease, may be more susceptible to severe COVID-19 due to increased levels of beta-amyloid (Aβ). Aβ(1-42) specifically binds to viral proteins of SARS-CoV-2, such as the spike protein S1 subunit and ACE2 receptor, potentially enhancing viral entry into cells and increasing inflammation. Further research is needed to explore the mechanisms underlying this interaction and investigate the potential benefits of reducing Aβ(1-42) levels in combating COVID-19 and AD.