Epidemiological and experimental evidence suggests that Herpes Simplex virus type-1 (HSV-1) infection is a risk factor for Alzheimer's disease (AD). We recently set up an in vivo model (female BALB/c mice) of multiple HSV-1 reactivations exhibiting typical AD hallmarks, including accumulation of amyloid-? protein, tau hyperphosphorylation, and neuroinflammation in several brain areas (De Chiara et al., 2019). Here we used a similar experimental paradigm to investigate the impact of virus infection on synaptic function and memory in 5-month-old male C57/bl6 mice infected with HSV-1 and subjected to multiple reactivations in the brain. Results showed that synaptic plasticity at the hippocampal CA3-CA1 synapse, assessed by long-term potentiation protocol, was significantly reduced in brain slices from HSV-1-infected mice compared to mock-infected ones: the fEPSP amplitude was 58.2±7.9% of the baseline (n=16 slices from 5 mice) vs. 97.6±10.8% (n=17 slices from 7 mice, p<0.05), respectively. The HSV-1-infected mice also exhibited memory impairment, assessed by the novel object recognition (NOR) and fear conditioning tests. Specifically, in the NOR paradigm the preference index was 57.5±2.8% (n=14) vs. 65.8±2.4% (n=16) in HSV-1- and mock-infected mice, respectively (p<0.05). The contextual fear memory was also reduced in infected mice: freezing behavior was 30.4±3.0% (n=14) in HSV-1-infected mice and 41.9±3.1% (n=15) in controls (p<0.05). Moreover, Western blot and immunohistochemistry experiments revealed a significant reduction of synapsin and synaptophysin protein levels in hippocampi of infected C57/bl6 mice (-50% [n=7 for each condition] and -30% [n=7 for mock and n=6 for HSV-1] respectively, vs. mock, p<0.05). Functional, behavioral and molecular alterations correlated with the presence of HSV-1 in mice brains, assessed by real time PCR and immunohistochemistry for the early viral protein ICP4. Collectively, our results suggest that HSV-1 reactivations into the brain induce an AD-like phenotype consisting in synaptic plasticity and memory impairment in C57/bl6 mice. These findings further support the HSV-1 role in AD pathophysiology.
A mouse model of recurrent Herpes Simplex virus type-1 infections exhibits synaptic dysfunction and memory impairment reminiscent of Alzheimer's disease phenotype
G DE CHIARA;
2019
Abstract
Epidemiological and experimental evidence suggests that Herpes Simplex virus type-1 (HSV-1) infection is a risk factor for Alzheimer's disease (AD). We recently set up an in vivo model (female BALB/c mice) of multiple HSV-1 reactivations exhibiting typical AD hallmarks, including accumulation of amyloid-? protein, tau hyperphosphorylation, and neuroinflammation in several brain areas (De Chiara et al., 2019). Here we used a similar experimental paradigm to investigate the impact of virus infection on synaptic function and memory in 5-month-old male C57/bl6 mice infected with HSV-1 and subjected to multiple reactivations in the brain. Results showed that synaptic plasticity at the hippocampal CA3-CA1 synapse, assessed by long-term potentiation protocol, was significantly reduced in brain slices from HSV-1-infected mice compared to mock-infected ones: the fEPSP amplitude was 58.2±7.9% of the baseline (n=16 slices from 5 mice) vs. 97.6±10.8% (n=17 slices from 7 mice, p<0.05), respectively. The HSV-1-infected mice also exhibited memory impairment, assessed by the novel object recognition (NOR) and fear conditioning tests. Specifically, in the NOR paradigm the preference index was 57.5±2.8% (n=14) vs. 65.8±2.4% (n=16) in HSV-1- and mock-infected mice, respectively (p<0.05). The contextual fear memory was also reduced in infected mice: freezing behavior was 30.4±3.0% (n=14) in HSV-1-infected mice and 41.9±3.1% (n=15) in controls (p<0.05). Moreover, Western blot and immunohistochemistry experiments revealed a significant reduction of synapsin and synaptophysin protein levels in hippocampi of infected C57/bl6 mice (-50% [n=7 for each condition] and -30% [n=7 for mock and n=6 for HSV-1] respectively, vs. mock, p<0.05). Functional, behavioral and molecular alterations correlated with the presence of HSV-1 in mice brains, assessed by real time PCR and immunohistochemistry for the early viral protein ICP4. Collectively, our results suggest that HSV-1 reactivations into the brain induce an AD-like phenotype consisting in synaptic plasticity and memory impairment in C57/bl6 mice. These findings further support the HSV-1 role in AD pathophysiology.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
