amyloid-beta-peptides and Herpes-Simplex

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Central Nervous System Infections; Cerebrospinal Fluid; DNA, Viral; Herpes Simplex; Herpes Zoster; Herpesvirus 1, Human; Herpesvirus 3, Human; Humans; Peptide Fragments; tau Proteins

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.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Cell Line, Tumor; Coculture Techniques; Culture Media, Conditioned; Herpes Simplex; Herpesvirus 1, Human; Humans; Interferon-alpha; Interleukin-1beta; Neuroglia; Neurons; Peptide Fragments; Tumor Necrosis Factor-alpha; Virus Replication

Herpes simplex virus (HSV) types 1 and 2 are neurotropic viruses that establish lifelong latent infections in neurons. Mounting evidence suggests that HSV-1 infection is involved in the pathogenesis of Alzheimer's disease (AD). The relationships between other herpesvirus infections and events associated with neurodegeneration have not, however, been extensively studied. The present work reports that HSV-2 infection leads to the strong accumulation of hyperphosphorylated tau and the amyloid-β peptides Aβ40 and Aβ42 (all major pathological hallmarks of AD) in human SK-N-MC neuroblastoma cells. Infection is also associated with a marked reduction in the amount of Aβ40 secreted and in the proteolytic fragments of the amyloid-β precursor protein (APP) (secreted APPα and the α-C-terminal fragment). These results indicate that HSV-2 infection inhibits the nonamyloidogenic pathway of APP processing and impairs Aβ secretion in these cells. In addition, HSV-2 induces the accumulation of intracellular autophagic compartments containing Aβ due to a failure in the late stages of autophagy. To our knowledge, this is the first report to show that HSV-2 infection strongly alters the tau phosphorylation state, APP processing, and autophagic process in human neuroblastoma cells, leading to the appearance of AD-like neurodegeneration markers.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Autophagy; Cell Line, Tumor; Herpes Simplex; Herpesvirus 2, Human; Humans; Neuroblastoma; Peptide Fragments; Phosphorylation; tau Proteins