We previously demonstrated that herpes simplex virus-1 (HSV-1) infection in neurons causes marked changes in their excitability and intracellular Ca2+ content, together with the phosphorylation and amyloidogenic processing of amyloid precursor protein (APP), (De Chiara et al, 2010, Piacentini et al, 2011, Civitelli et al 2015). These data support the hypothesis that recurrent HSV-1 reactivations may contribute to neurodegeneration typical of Alzheimer's disease (AD), causing repeated cycles of viral infection into the brain. To further explore such an hypothesis, we established a murine model of recurrent HSV-1 infection, closely resembling those occurring in humans: 1 month old female BALB/c mice were inoculated via snout abrasion with a sublethal doses of HSV-1 (F strain, 1x10e6 plaque forming unit), or a mock solution as control. Viral reactivation was periodically induced by thermal stress. HSV-1 spreading to the brain, as well as AD-like neuropathological hallmarks were analyzed in mice during the course of aging. Following virus reactivations we found: 1) viral TK and ICP4 genes (markers of viral infection and active replication, respectively) in cortex and hippocampal tissues, indicating that HSV-1 is able to reach and actively replicate in those brain regions mostly affected during AD; 2) accumulation of ?-amyloid peptides (A?s) and other APP proteolytic fragments, together with altered tau phosphorylation and signs of neuroinflammation in hippocampus and cortex of aged animals; 3) significant impairments in mouse performance in the novel object recognition and Y Maze behavioral tests. Overall, these results strongly support the hypothesis that recurrent HSV-1 infections may contribute to neurodegeneration typical of AD.
Recurrent herpes simplex virus-1 (HSV1) infections in mice cause signs of neurodegeneration and cognitive deficits
2015
Abstract
We previously demonstrated that herpes simplex virus-1 (HSV-1) infection in neurons causes marked changes in their excitability and intracellular Ca2+ content, together with the phosphorylation and amyloidogenic processing of amyloid precursor protein (APP), (De Chiara et al, 2010, Piacentini et al, 2011, Civitelli et al 2015). These data support the hypothesis that recurrent HSV-1 reactivations may contribute to neurodegeneration typical of Alzheimer's disease (AD), causing repeated cycles of viral infection into the brain. To further explore such an hypothesis, we established a murine model of recurrent HSV-1 infection, closely resembling those occurring in humans: 1 month old female BALB/c mice were inoculated via snout abrasion with a sublethal doses of HSV-1 (F strain, 1x10e6 plaque forming unit), or a mock solution as control. Viral reactivation was periodically induced by thermal stress. HSV-1 spreading to the brain, as well as AD-like neuropathological hallmarks were analyzed in mice during the course of aging. Following virus reactivations we found: 1) viral TK and ICP4 genes (markers of viral infection and active replication, respectively) in cortex and hippocampal tissues, indicating that HSV-1 is able to reach and actively replicate in those brain regions mostly affected during AD; 2) accumulation of ?-amyloid peptides (A?s) and other APP proteolytic fragments, together with altered tau phosphorylation and signs of neuroinflammation in hippocampus and cortex of aged animals; 3) significant impairments in mouse performance in the novel object recognition and Y Maze behavioral tests. Overall, these results strongly support the hypothesis that recurrent HSV-1 infections may contribute to neurodegeneration typical of AD.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
