2. Academic Validation
  3. Differential Cytokine Responses of APOE3 and APOE4 Blood-brain Barrier Cell Types to SARS-CoV-2 Spike Proteins

Differential Cytokine Responses of APOE3 and APOE4 Blood-brain Barrier Cell Types to SARS-CoV-2 Spike Proteins

  • J Neuroimmune Pharmacol. 2024 May 21;19(1):22. doi: 10.1007/s11481-024-10127-9.
Juliana C S Chaves 1 2,  Laura A Milton 1,  Romal Stewart 1,  Tarosi Senapati 3,  Laura M Rantanen 1 2,  Joanna M Wasielewska 1 4,  Serine Lee 1,  Damián Hernández 5,  Lachlan McInnes 6,  Hazel Quek 1 2 7,  Alice Pébay 5 8,  Paul S Donnelly 6,  Anthony R White 1 7,  Lotta E Oikari 9 10
Affiliations

Affiliations

  • 1 Mental Health and Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane (QLD), Australia.
  • 2 Queensland University of Technology, Brisbane (QLD), Australia.
  • 3 The University of Queensland, Brisbane (QLD), Australia.
  • 4 Faculty of Medicine, The University of Queensland, Brisbane (QLD), Australia.
  • 5 Department of Anatomy and Physiology, The University of Melbourne, Parkville (VIC), Australia.
  • 6 School of Chemistry, Bio21 Institute for Molecular Science and Biotechnology, The University of Melbourne, Parkville (VIC), Australia.
  • 7 School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane (QLD), Australia.
  • 8 Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville (VIC), Australia.
  • 9 Mental Health and Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane (QLD), Australia. Lotta.Oikari@qimrberghofer.edu.au.
  • 10 Queensland University of Technology, Brisbane (QLD), Australia. Lotta.Oikari@qimrberghofer.edu.au.
PMID: 38771543 DOI: 10.1007/s11481-024-10127-9
Abstract

SARS-CoV-2 Spike Proteins have been shown to cross the blood-brain barrier (BBB) in mice and affect the integrity of human BBB cell models. However, the effects of SARS-CoV-2 Spike Proteins in relation to sporadic, late onset, Alzheimer's disease (AD) risk have not been extensively investigated. Here we characterized the individual and combined effects of SARS-CoV-2 spike protein subunits S1 RBD, S1 and S2 on BBB cell types (induced brain endothelial-like cells (iBECs) and astrocytes (iAstrocytes)) generated from induced pluripotent stem cells (iPSCs) harboring low (APOE3 carrier) or high (APOE4 carrier) relative Alzheimer's risk. We found that treatment with spike proteins did not alter iBEC integrity, although they induced the expression of several inflammatory cytokines. iAstrocytes exhibited a robust inflammatory response to SARS-CoV-2 spike protein treatment, with differences found in the levels of cytokine secretion between spike protein-treated APOE3 and APOE4 iAstrocytes. Finally, we tested the effects of potentially anti-inflammatory drugs during SARS-CoV-2 spike protein exposure in iAstrocytes, and discovered different responses between spike protein treated APOE4 iAstrocytes and APOE3 iAstrocytes, specifically in relation to IL-6, IL-8 and CCL2 secretion. Overall, our results indicate that APOE3 and APOE4 iAstrocytes respond differently to anti-inflammatory drug treatment during SARS-CoV-2 spike protein exposure with potential implications to therapeutic responses.

Keywords

Alzheimer’s disease; Apolipoprotein E; Astrocyte; Blood–brain barrier; Brain endothelial cell; SARS-CoV-2.

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