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

Int J Mol Sci. 2021 Jul 30;22(15):8226. doi: 10.3390/ijms22158226.


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, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ1-42, but not Aβ1-40, 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 Aβ1-42. Furthermore, Aβ1-42 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 Aβ1-42 show that the clearance of Aβ1-42 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-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ1-42 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 Aβ1-42 in the blood is beneficial to the fight against COVID-19 and AD.

Keywords: ACE2; Alzheimer’s disease; Aβ; COVID-19; SARS-CoV-2 spike protein.

MeSH terms

  • A549 Cells
  • Alzheimer Disease / complications
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Animals
  • COVID-19 / complications
  • COVID-19 / metabolism
  • Chlorocebus aethiops
  • Humans
  • Interleukin-6 / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism*
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • SARS-CoV-2 / enzymology*
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / metabolism*
  • Vero Cells
  • Virus Internalization


  • Amyloid beta-Peptides
  • Interleukin-6
  • Peptide Fragments
  • Protein Subunits
  • Spike Glycoprotein, Coronavirus
  • amyloid beta-protein (1-42)
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2