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

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.

Differential Phenotypes of Myeloid-Derived Suppressor and T Regulatory Cells and Cytokine Levels in Amnestic Mild Cognitive Impairment Subjects Compared to Mild Alzheimer Diseased Patients

“…We have previously postulated that in the case of aMCI subjects, these cells respond to some still unidentified challenge that may originate from chronic viral, bacterial, or fungal infections. The recent demonstration that beta amyloid peptides, the most important component of the characteristic amyloid plaques in AD, possess antimicrobial properties (12–14) is consistent with this notion. Overall, these observations have raised the level of interest in immune changes associated with the development and progression of AD (9).…”

Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection

“…This suggests Aβ binding of viral glycoproteins may not be the sole pathway mediating targeting of herpesviridae . Consistent with alternative/complementary herpes targeting pathways, Bourgade et al ., 2016 report HSV1 inhibition mediated by binding of a proximal region of gB with high sequence homology to Aβ (Bourgade et al, 2016). …”

“…However, mounting data suggest this long-standing model for Aβ pathogenesis requires revision. Recent findings have identified Aβ as an antimicrobial peptide (AMP), and suggest Aβ deposition may be a protective innate immune response to infection (Bourgade et al, 2015; Bourgade et al, 2016; Kumar et al, 2016; Soscia et al, 2010; White et al, 2014). A physiological role for Aβ as an AMP is also consistent with the peptide’s remarkably high sequence conservation across multiple phyla - the human Aβ sequence is at least 400 million years old and is found in 60–70 % of vertebrate species (Luna et al, 2013).…”

Role of neuroinflammation in neurodegeneration: new insights

“…It was recently demonstrated that Aβ protects against C. albicans infection in glial cells in vitro and in nematodes in vivo [69]. In addition, Aβ inhibits HSV-1 viral replication in vitro, and protects mice from Salmonella Typhimurium infection in vivo, which led the authors of both studies to conclude that Aβ may have a previously unknown protective role in innate immunity, along with the pathogenic characteristics that are extremely well studied [69, 70]. …”