Several literature reports suggested that herpes simplex virus type 1 (HSV-1) triggers neurodegenerative processes that are reminiscent of Alzheimer's disease (AD), a neurodegenerative disorder characterized by a progressive decline in cognitive function and the accumulation in the brain of amyloid-? peptides (A?s), hyperphosphorylated forms of tau protein, high levels of oxidative stress markers and neuroinflammation. However, a cause-effect relationship between the multiple HSV-1 reactivations characterizing the human disease and the development of an AD-like phenotype has yet to be demonstrated. Hence, we set up a mouse model of recurrent HSV-1 infection and investigated the appearance and accumulation over time of biochemical and functional AD markers. Methods 6-8 week-old BALB/c mice were infected by labial HSV-1 inoculation and subsequently subjected to thermal stress (TS) every 6-8 weeks over the next 10 months to induce repeated virus reactivations. Virus spreading and replication into the brain were assessed by PCR amplification of viral gene/mRNA, immunofluorescence detection of viral protein and infectious virus isolation from brain tissues. Immunohistochemistry, western blot (WB), ELISA assay as well as redox proteomic were used to reveal AD hallmarks in the brain following repeated TSs. Novel object Recognition (NOR) and Y-Maze behavioral test were used to assess cognitive dysfunction. Results We found that multiple HSV-1 reactivations triggered, in mouse brain, the accumulation of AD hallmarks, including A?, hyperphosphorylated tau and neuroinflammation. These AD hallmarks were paralleled by increased levels of 4-hydroxynonenal (HNE, marker of lipid. peroxidation), 3-nitrotyrosine (3NT, marker of protein nytrosylation) and protein carboxylation, indicating generalized conditions of oxidative stress. Specifically we found the alteration in the level of 13 HNE-modified proteins involved in energy metabolism, protein folding, cell structure, and signal transduction, cognitive dysfunction. Accordingly, behavioral tests evidenced cognitive deficits that became greater following several TSs, thus suggesting their correlation with the progressive accumulation of virus-dependent AD-like damages. Conclusions Our findings support the view that multiple HSV-1 reactivations, causing mild but repeated viral spreading and replication in the central nervous system, may be a risk factor for AD.
Recurrent Herpes Simplex Virus-1 infection induces molecular hallmarks of neurodegeneration and cognitive deficits in mice
GIOVANNA DE CHIARA;
2018
Abstract
Several literature reports suggested that herpes simplex virus type 1 (HSV-1) triggers neurodegenerative processes that are reminiscent of Alzheimer's disease (AD), a neurodegenerative disorder characterized by a progressive decline in cognitive function and the accumulation in the brain of amyloid-? peptides (A?s), hyperphosphorylated forms of tau protein, high levels of oxidative stress markers and neuroinflammation. However, a cause-effect relationship between the multiple HSV-1 reactivations characterizing the human disease and the development of an AD-like phenotype has yet to be demonstrated. Hence, we set up a mouse model of recurrent HSV-1 infection and investigated the appearance and accumulation over time of biochemical and functional AD markers. Methods 6-8 week-old BALB/c mice were infected by labial HSV-1 inoculation and subsequently subjected to thermal stress (TS) every 6-8 weeks over the next 10 months to induce repeated virus reactivations. Virus spreading and replication into the brain were assessed by PCR amplification of viral gene/mRNA, immunofluorescence detection of viral protein and infectious virus isolation from brain tissues. Immunohistochemistry, western blot (WB), ELISA assay as well as redox proteomic were used to reveal AD hallmarks in the brain following repeated TSs. Novel object Recognition (NOR) and Y-Maze behavioral test were used to assess cognitive dysfunction. Results We found that multiple HSV-1 reactivations triggered, in mouse brain, the accumulation of AD hallmarks, including A?, hyperphosphorylated tau and neuroinflammation. These AD hallmarks were paralleled by increased levels of 4-hydroxynonenal (HNE, marker of lipid. peroxidation), 3-nitrotyrosine (3NT, marker of protein nytrosylation) and protein carboxylation, indicating generalized conditions of oxidative stress. Specifically we found the alteration in the level of 13 HNE-modified proteins involved in energy metabolism, protein folding, cell structure, and signal transduction, cognitive dysfunction. Accordingly, behavioral tests evidenced cognitive deficits that became greater following several TSs, thus suggesting their correlation with the progressive accumulation of virus-dependent AD-like damages. Conclusions Our findings support the view that multiple HSV-1 reactivations, causing mild but repeated viral spreading and replication in the central nervous system, may be a risk factor for AD.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
