Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model

Article type: Research Article

Authors: Bourgade, Karine^a | Le Page, Aurélie^a | Bocti, Christian^b | Witkowski, Jacek M.^c | Dupuis, Gilles^d | Frost, Eric H.^e | Fülöp Jr., Tamás^{f; *}

Affiliations: [a] Research Center on Aging, Graduate Program in Immunology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada | [b] Department of Medicine, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada | [c] Department of Pathophysiology, Medical University of Gdansk, Poland | [d] Department of Biochemistry, Graduate Program in Immunology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada | [e] Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada | [f] Department of Medicine, Research Center on Aging, Graduate Program in Immunology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada

Correspondence: [*] Correspondence to: Tamás Fülöp, MD, PhD, Research Center on Aging, Faculty of Medicine and Health Sciences, University of Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC, J1H 5N4, Canada. Tel.: +1 819 780 2220; Fax: +1 819 829 7141; E-mail: Tamas.Fulop@Usherbrooke.ca.

Abstract: Senile amyloid plaques are one of the main hallmarks of Alzheimer’s disease (AD). They correspond to insoluble deposits of amyloid-β peptides (Aβ) and are responsible for the inflammatory response and neurodegeneration that lead to loss of memory. Recent data suggest that Aβ possess antimicrobial and anti-viral activity in vitro. Here, we have used cocultures of neuroglioma (H4) and glioblastoma (U118-MG) cells as a minimal in vitro model to investigate whether Aβ is produced by neuroglioma cells and whether this could result in protective anti-viral activity against HSV-1 infection. Results showed that H4 cells secreted Aβ42 in response to HSV-1 challenge and that U118-MG cells could rapidly internalize Aβ42. Production of pro-inflammatory cytokines TNFα and IL-1β by H4 and U118-MG cells occurred under basal conditions but infection of the cells with HSV-1 did not significantly upregulate production. Both cell lines produced low levels of IFNα. However, extraneous Aβ42 induced strong production of these cytokines. A combination of Aβ42 and HSV-1 induced production of pro-inflammatory cytokines TNFα and IL-1β, and IFNα in the cell lines. The reported anti-viral protection of Aβ42 was revealed in transfer experiments involving conditioned medium (CM) of HSV-1-infected H4 cells. CM conferred Aβ-dependent protection against HSV-1 replication in de novo cultures of H4 cells challenged with HSV-1. Type 1 interferons did not play a role in these assays. Our data established that H4 neuroglioma cells produced Aβ42 in response to HSV-1 infection thus inhibiting secondary replication. This mechanism may play a role in the etiology of AD.

Keywords: Alzheimer’s disease, amyloid-β peptides, cocultures, glial cells, herpes simplex virus-1 (HSV-1), neuronal cells, viral replication inhibition

DOI: 10.3233/JAD-150652

Journal: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1227-1241, 2016