Influenza A (H1N1)pdm infection exacerbates behavioral, cognitive, and synaptic impairments in 5xFAD mice

Alzheimer's disease (AD) is characterized by progressive cognitive decline, synaptic dysfunction, and neuroinflammation, which may be influenced by systemic factors such as infection. The present study aimed to investigate the effects of prior influenza A (H1N1)pdm infection on behavioral, synaptic, and neuroinflammatory alterations in the 5xFAD mouse model of AD. Mice were intranasally infected at 2 months of age and underwent behavioral assessment from 7 months of age using tests of social, affective, exploratory, and cognitive function. Hippocampal synaptic function and structure were assessed by CA1 long-term potentiation (LTP) recordings and dendritic spine analysis, while neuroinflammation and amyloid pathology were evaluated by Western blot and immunohistochemistry. 5xFAD mice exhibited impairments in hippocampus-dependent memory, social behavior, and affective responses. Prior H1N1pdm infection modulated these phenotypes, resulting in increased depressive-like behavior in the tail suspension test and alterations in exploratory and social activity. At the synaptic level, reduced LTP and decreased dendritic spine density were observed in 5xFAD mice, along with a shift toward immature spine morphology. Viral infection induced similar synaptic alterations in wild-type mice but did not further exacerbate synaptic deficits in 5xFAD animals. Both amyloid pathology and infection were associated with increased astrocytic and microglial activation, with the strongest neuroinflammatory response detected in infected 5xFAD mice. Overall, prior H1N1pdm infection altered behavioral and neuroinflammatory phenotypes but did not further aggravate the already established synaptic deficits in 5xFAD mice. These findings support a non-additive interaction between systemic inflammation and neurodegenerative pathology and may help explain the heterogeneous consequences of viral infection in older individuals with cognitive impairment.