The neurotropic Herpes Simplex-1 (HSV-1) virus is able to establish a lifelong latent infection in trigeminal ganglion that is usually followed by several periodic reactivations. A growing body of evidence suggests HSV-1 as one of the potential risk factors for Alzheimer disease (AD). In fact, both epidemiological and experimental data linked HSV-1 recurrent infections to the appearance of the biochemical AD hallmarks, such as amyloid plaques and neurofibrillary tangles that are mainly constituted by ?-amyloid peptides (A?s) and hyperphosphorylated tau, respectively. We recently showed marked changes in neuronal excitability and intracellular Ca2+ signalling in cortical neurons following HSV-1 infection. In our experimental models, these effects caused, in turn, the phosphorylation of amyloid precursor protein (APP) and its amyloidogenic processing in multiple fragments. These include Aßs, both in monomeric and oligomeric forms, and APP C-terminal fragments (AICD), whose neurotoxic properties have been previously described. By using in vitro and in vivo experimental models of infection, our studies were then aimed at investigating: i) the biological effects of AICD produced in neurons after HSV-1 infection; ii) the ability of HSV-1 to reach the brain and to induce signs of neurodegeneration following viral reactivations. We found that HSV-1 led to the accumulation and nuclear translocation of AICD in neurons, where it binds the promoter region of Neprilysin (NEP) and glycogen synthase kinase-3 beta (GSK3?) genes, whose products play a role in A? clearance and tau phosphorylation, respectively. Time course analysis of NEP and GSK3? expression at mRNA and protein level demonstrated that they are differently modulated during infection: after an early induction in their expression and enzymatic activity, they were down-regulated later in infection, suggesting that HSV-1 induces early upstream intraneuronal events that may lead to A? deposition and tau hyperphosphorylation as final outcomes. For in vivo studies, we first established a murine model of recurrent HSV-1 infection, closely resembling those occurring in humans. Amplification of specific viral genes in different brain areas demonstrated that, following viral reactivations, the virus is able to reach and actively replicate in brain regions mostly affected during AD. Interestingly, in these areas we found signs of neurodegeneration. Further studies are in progress to demonstrate in detail the causal relationship between multiple viral reactivations, viral replication in the brain and the appearance of molecular and functional hallmarks of AD. Overall, these results strongly support the hypothesis that recurrent HSV-1 infections may contribute to neurodegeneration.
HERPES SIMPLEX VIRUS-1 INDUCED NEURODEGENERATIVE MARKERS IN NEURONS AND IN BRAIN
GIOVANNA DE CHIARA
2015
Abstract
The neurotropic Herpes Simplex-1 (HSV-1) virus is able to establish a lifelong latent infection in trigeminal ganglion that is usually followed by several periodic reactivations. A growing body of evidence suggests HSV-1 as one of the potential risk factors for Alzheimer disease (AD). In fact, both epidemiological and experimental data linked HSV-1 recurrent infections to the appearance of the biochemical AD hallmarks, such as amyloid plaques and neurofibrillary tangles that are mainly constituted by ?-amyloid peptides (A?s) and hyperphosphorylated tau, respectively. We recently showed marked changes in neuronal excitability and intracellular Ca2+ signalling in cortical neurons following HSV-1 infection. In our experimental models, these effects caused, in turn, the phosphorylation of amyloid precursor protein (APP) and its amyloidogenic processing in multiple fragments. These include Aßs, both in monomeric and oligomeric forms, and APP C-terminal fragments (AICD), whose neurotoxic properties have been previously described. By using in vitro and in vivo experimental models of infection, our studies were then aimed at investigating: i) the biological effects of AICD produced in neurons after HSV-1 infection; ii) the ability of HSV-1 to reach the brain and to induce signs of neurodegeneration following viral reactivations. We found that HSV-1 led to the accumulation and nuclear translocation of AICD in neurons, where it binds the promoter region of Neprilysin (NEP) and glycogen synthase kinase-3 beta (GSK3?) genes, whose products play a role in A? clearance and tau phosphorylation, respectively. Time course analysis of NEP and GSK3? expression at mRNA and protein level demonstrated that they are differently modulated during infection: after an early induction in their expression and enzymatic activity, they were down-regulated later in infection, suggesting that HSV-1 induces early upstream intraneuronal events that may lead to A? deposition and tau hyperphosphorylation as final outcomes. For in vivo studies, we first established a murine model of recurrent HSV-1 infection, closely resembling those occurring in humans. Amplification of specific viral genes in different brain areas demonstrated that, following viral reactivations, the virus is able to reach and actively replicate in brain regions mostly affected during AD. Interestingly, in these areas we found signs of neurodegeneration. Further studies are in progress to demonstrate in detail the causal relationship between multiple viral reactivations, viral replication in the brain and the appearance of molecular and functional hallmarks of AD. Overall, these results strongly support the hypothesis that recurrent HSV-1 infections may contribute to neurodegeneration.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
