Abstract
Amyloid plaques, the hallmark of Alzheimer’s disease (AD), contain fibrillar β-amyloid (Aβ) 1-40 and 1-42 peptides. Herpes simplex virus 1 (HSV-1) has been implicated as a risk factor for AD and found to co-localize within amyloid plaques. Aβ 1-40 and Aβ 1-42 display anti-bacterial, anti-yeast and anti-viral activities. Here, fibroblast, epithelial and neuronal cell lines were exposed to Aβ 1-40 or Aβ 1-42 and challenged with HSV-1. Quantitative analysis revealed that Aβ 1-40 and Aβ 1-42 inhibited HSV-1 replication when added 2 h prior to or concomitantly with virus challenge, but not when added 2 or 6 h after virus addition. In contrast, Aβ 1-40 and Aβ 1-42 did not prevent replication of the non-enveloped human adenovirus. In comparison, antimicrobial peptide LL-37 prevented HSV-1 infection independently of its sequence of addition. Our findings showed also that Aβ 1-40 and Aβ 1-42 acted directly on HSV-1 in a cell-free system and prevented viral entry into cells. The sequence homology between Aβ and a proximal transmembrane region of HSV-1 glycoprotein B suggested that Aβ interference with HSV-1 replication could involve its insertion into the HSV-1 envelope. Our data suggest that Aβ peptides represent a novel class of antimicrobial peptides that protect against neurotropic enveloped virus infections such as HSV-1. Overproduction of Aβ peptide to protect against latent herpes viruses and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of AD.
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This work was supported by Grants-in-aid from the Canadian Institute of Health Research (CIHR) (No. 106634), the Université de Sherbrooke, and the Research Center on Aging.
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Fig. S1. Time-dependent replication of HSV-1 and HAd5 in MRC-5 and A549 cells, respectively. MRC-5 and A549 cells were exposed to (A) HSV-1 or (B) HAd5 using an initial 0.01 ID50 per cell. Viral replication was analyzed by real-time PCR at the indicated times. Data are a combination of 2 independent experiments performed in duplicate and are shown as the mean ± SEM. Cp designates the crossing point which corresponds to the number of qPCR cycles needed to detect fluorescence of each sample. Fig. S2. Sequence homology between Aβ 1-42 and a transmembrane region of HSV-1 gB. Amino acid sequence alignment of Aβ 1-42 and a transmembrane region (positions 713 – 763) of HSV-1 gB using Clustal Omega shareware (http://expasy.org/proteomics). Identical amino acid residues are indicated by vertical lines and amino acids possessing similar properties, by dashed vertical lines. Adapted with permission from Cribbs et al. (Biochemistry, 39 (2000) 5988-5,994). Copyright 2000, American Chemical Society. Supplementary material 1 (PDF 117 kb)
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Bourgade, K., Garneau, H., Giroux, G. et al. β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology 16, 85–98 (2015). https://doi.org/10.1007/s10522-014-9538-8
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DOI: https://doi.org/10.1007/s10522-014-9538-8