Recurrent mild SARS-CoV-2 infection affects the lung-brain axis in wild type and Alzheimer’s mice

The lung-brain axis, describing the complex communication between the respiratory and central nervous systems (CNS), has gained attention due to the increasing number of individuals experiencing long-term neurological symptoms following respiratory infections. Since the emergence of Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), millions of individuals have developed persistent symptoms collectively known as long-COVID. Among these, cognitive impairment, fatigue, and ‘brain fog’ are frequently reported. Clinical observations also suggest that SARS-CoV-2 infection may increase the risk of developing neurodegenerative conditions such as Alzheimer’s disease (AD). However, the biological mechanisms linking repeated respiratory infections and brain pathology remain poorly understood. In this study, we investigated how recurrent respiratory infection with distinct SARS-CoV-2 variants affects brain health in wild type and AD mice. Hereto, wild type and knock-in App NL−G−F Alzheimer mice, crossed into a K18-hACE2 background, were infected sequentially with two antigenically distinct variants of SARS-CoV-2 to mimic the repeated exposure experienced by many individuals during the pandemic. Two weeks after the second viral exposure, we observed no notable changes in the number or reactive state of microglial cells and astrocytes, the brain's key immune cells. In contrast, we observed a hippocampal consistent reduction in synaptic integrity in infected mice. In AD mice, repeated infection also led to increased accumulation of amyloid plaques, a hallmark of AD pathology. Our findings indicate that repeated mild SARS-CoV-2 infections can impair neuronal function and worsen brain pathology in a susceptible mouse model. This work highlights the importance of the lung-brain axis in understanding the long-term neurological consequences of respiratory viral infections and suggests that individuals at risk for neurodegenerative diseases may be particularly sensitive to repeated viral exposure.