Several evidence suggest HSV-1 as a potential risk factors for Alzheimer disease (AD), a neurodegenerative disorder characterized by the accumulation in the brain of beta-amyloid peptides (Abetas) and neurofibrillary tangles (mainly composed by hyperphosphorylated tau), high level of oxidative stress markers and neuroinflammation (De Chiara et al, 2012). Herein we design in vitro and in vivo study to clarify the role of oxidative stress in virus-induced neurodegeneration. Methods: Levels of oxidative stress marker, i.e. reactive oxygen (ROS) and 4-hydroxynonenal (HNE), were measured in HSV-1-infected neuronal cells by fluorimetry and western blotting (wb). BALB/c mice were inoculated via snout abrasion with HSV-1, virus reactivation was periodically induced by thermal stress, and virus replication in the brain was verified through PCR and RT-PCR analysis of viral TK gene and ICP4 mRNA. AD-like hallmarks were analyzed in brain tissues by Bio-plex technology, immunofluorescence, wb. Results: We found that HSV-1 induces in neuronal cells a significant increase in ROS and HNE levels 4h after virus infection. This timing is consistent with our previous data showing the activation of redox-regulated pathway inducing A? production. Similar effects were also found in primary culture of murine cortical neurons following HSV-1 infection. These results prompted us to investigate whether virus-induced oxidative damages may accumulate following recurrent HSV-1 infections. We found that repeated HSV-1 reactivations induce in mouse brains: 1) virus spreading and replication in those brain region most affected in AD (i.e. cortex and hippocampus), as assessed by amplification of viral TK and ICP4 genes; 2) a significant increase in HNE levels and nitrosylated proteins in cortical tissues; 3) enhanced levels of IL-6 and IL-1??cytokines and gliosis. Discussion and Conclusions: These data, together with those showing accumulation of Abetas and altered tau phosphorylation in HSV-1-infected mouse brains (De Chiara et al, manuscript in preparation), strongly support the hypothesis that repeated HSV-1 infections may contribute to the neurodegeneration typical of AD and suggest the involvement of the oxidative stress elicited by the virus.
Herpes Simplex Virus Type 1 (HSV-1) infection, neuroinflammation and neurodegeneration: a possible role for oxidative stress?
G De Chiara
2016
Abstract
Several evidence suggest HSV-1 as a potential risk factors for Alzheimer disease (AD), a neurodegenerative disorder characterized by the accumulation in the brain of beta-amyloid peptides (Abetas) and neurofibrillary tangles (mainly composed by hyperphosphorylated tau), high level of oxidative stress markers and neuroinflammation (De Chiara et al, 2012). Herein we design in vitro and in vivo study to clarify the role of oxidative stress in virus-induced neurodegeneration. Methods: Levels of oxidative stress marker, i.e. reactive oxygen (ROS) and 4-hydroxynonenal (HNE), were measured in HSV-1-infected neuronal cells by fluorimetry and western blotting (wb). BALB/c mice were inoculated via snout abrasion with HSV-1, virus reactivation was periodically induced by thermal stress, and virus replication in the brain was verified through PCR and RT-PCR analysis of viral TK gene and ICP4 mRNA. AD-like hallmarks were analyzed in brain tissues by Bio-plex technology, immunofluorescence, wb. Results: We found that HSV-1 induces in neuronal cells a significant increase in ROS and HNE levels 4h after virus infection. This timing is consistent with our previous data showing the activation of redox-regulated pathway inducing A? production. Similar effects were also found in primary culture of murine cortical neurons following HSV-1 infection. These results prompted us to investigate whether virus-induced oxidative damages may accumulate following recurrent HSV-1 infections. We found that repeated HSV-1 reactivations induce in mouse brains: 1) virus spreading and replication in those brain region most affected in AD (i.e. cortex and hippocampus), as assessed by amplification of viral TK and ICP4 genes; 2) a significant increase in HNE levels and nitrosylated proteins in cortical tissues; 3) enhanced levels of IL-6 and IL-1??cytokines and gliosis. Discussion and Conclusions: These data, together with those showing accumulation of Abetas and altered tau phosphorylation in HSV-1-infected mouse brains (De Chiara et al, manuscript in preparation), strongly support the hypothesis that repeated HSV-1 infections may contribute to the neurodegeneration typical of AD and suggest the involvement of the oxidative stress elicited by the virus.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
