Introduction: A growing body of evidence suggest herpes simplex virus type 1 (HSV-1) as one of the potential risk factors for Alzheimer disease (AD), linking recurrent HSV-1 infections to the appearance of the biochemical hallmarks of this devastating disease. These include intra- and extra-neuronal accumulation of ?-amyloid peptides (A?s) and neurofibrillary tangles, mainly composed by hyperphosforilated tau. We previously demonstrated that HSV-1 productive infections cause marked changes in neuronal excitability and intracellular Ca2+ signaling modulating the phosphorylation of amyloid precursor protein (APP) and promoting its processing in various neurotoxic fragments, including A?s. Herein we designed in vivo studies to verify whether repeated reactivation of the virus, like those occurring in humans during life, lead to the accumulation of these toxic bricks in the brain and in turn to the appearance of an AD-like phenotype. Materials and Methods: 1 month old BALB/c mice were inoculated via snout abrasion with a sublethal doses of HSV-1. Viral reactivation was periodically induced by thermal stress. HSV-1 spreading to the brain and reactivations were analyzed in mice through PCR analysis of viral TK gene and RT-analysis of ICP4 mRNA. AD-like phenotype was analyzed in mice through: a) immunofluorescence and western blotting analysis of APP processing and tau phosphorylation; b) Y-MAZE and novel object recognition (NOR) behavioral tests. Results: Following virus reactivations we found: 1) viral TK and ICP4 genes (markers of viral infection and active reactivation respectively) in cortex and hippocampal tissues, indicating that HSV-1 is able to reach and replicate in those brain regions mostly affected during AD; 2)accumulation of 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 NOR and Y Maze behavioral tests.
Herpes simplex virus-1 and Alzheimer's disease
2015
Abstract
Introduction: A growing body of evidence suggest herpes simplex virus type 1 (HSV-1) as one of the potential risk factors for Alzheimer disease (AD), linking recurrent HSV-1 infections to the appearance of the biochemical hallmarks of this devastating disease. These include intra- and extra-neuronal accumulation of ?-amyloid peptides (A?s) and neurofibrillary tangles, mainly composed by hyperphosforilated tau. We previously demonstrated that HSV-1 productive infections cause marked changes in neuronal excitability and intracellular Ca2+ signaling modulating the phosphorylation of amyloid precursor protein (APP) and promoting its processing in various neurotoxic fragments, including A?s. Herein we designed in vivo studies to verify whether repeated reactivation of the virus, like those occurring in humans during life, lead to the accumulation of these toxic bricks in the brain and in turn to the appearance of an AD-like phenotype. Materials and Methods: 1 month old BALB/c mice were inoculated via snout abrasion with a sublethal doses of HSV-1. Viral reactivation was periodically induced by thermal stress. HSV-1 spreading to the brain and reactivations were analyzed in mice through PCR analysis of viral TK gene and RT-analysis of ICP4 mRNA. AD-like phenotype was analyzed in mice through: a) immunofluorescence and western blotting analysis of APP processing and tau phosphorylation; b) Y-MAZE and novel object recognition (NOR) behavioral tests. Results: Following virus reactivations we found: 1) viral TK and ICP4 genes (markers of viral infection and active reactivation respectively) in cortex and hippocampal tissues, indicating that HSV-1 is able to reach and replicate in those brain regions mostly affected during AD; 2)accumulation of 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 NOR and Y Maze behavioral tests.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
