MULTIPLE HERPES SIMPLEX VIRUS-1 (HSV-1) REACTIVATIONS INDUCE NEURODEGENERATIVE AND OXIDATIVE DAMAGES IN MOUSE BRAINS

A growing body of evidence supports the role of oxidative stress in Alzheimer's disease (AD) pathophysiology. Interestingly, HSV-1, a neurotropic virus able to establish a lifelong latent infection in trigeminal ganglion followed by periodic reactivations, has been reportedly linked both to AD and to oxidative stress conditions. Thus, we designed in vivo studies to investigate whether multiple HSV-1 reactivations induced in the brain the accumulation of oxidative stress hallmarks, particularly those correlated to AD. Oxidative stress marker levels, i.e. 4-hydroxynonenal (HNE, marker of lipid peroxidation), 3-nitrotyrosine (3NT, marker of protein nytrosylation) and carbonylated proteins, were measured in brains of mice undergone multiple HSV-1 reactivations by western blotting. In addition, redox proteomic was used to identify those HNE-modified proteins mostly modulated by recurrent HSV-1 reactivations into the brain. Following several cycle of viral reactivation, we found in mouse brains: 1) the presence of specific viral DNA and mRNA genes, indicating that HSV-1 is able to reach and replicate in those brain regions mostly affected during AD; 2) increased levels of HNE, 3-NT, and protein carbonylation, indicating generalized conditions of oxidative stress; 3) thirteen HNE-modified proteins whose levels were significantly modulated in the cortex of HSV-1 infected mice compared to control mice. Interestingly, all these proteins are involved in important cellular processes, such as energy metabolism, protein folding, cell structure, and signal transduction, suggesting that their oxidative modification may affect brain physiology. Some of these proteins are reported to be significantly HNE-modified in AD brains compared to matched controls. In addition, these mice showed several signs of neurodegeneration ). Overall, these data support the hypothesis that repeated HSV-1 reactivation into the brain may concur to neurodegeneration also inducing oxidative damages