SARS-CoV-2 spike protein induces cognitive deficit and anxiety-like behavior in mouse via non-cell autonomous hippocampal neuronal death

"Discussion

Many clinical reports of COVID-19 survivors suffering from various neurological and psychiatric symptoms such as cognitive decline and mood disorder undoubtedly show that SARS-CoV-2 affects the human CNS [central nervous system]. The initial assumption of direct SARS-CoV-2 infection in the brain was not supported by following studies; thus, the cellular and molecular mechanisms are still elusive. The recent discovery of the blood–brain barrier-penetrating SARS-CoV-2 spike protein offers a new possibility that the SARS-CoV-2-derived spike protein causes neurological or psychiatric symptoms observed in the COVID-19 survivors, which we tested in this study. We demonstrated that S1 protein administration into mice hippocampi led to cognitive decline and anxiety-like behavior. These data suggest that several neurological and psychiatric symptoms observed in COVID-19 patients can be mediated by the brain-penetrating S1 protein in the absence of direct CNS infection of SARS-CoV-2.

It is well known that the hippocampus is important for cognition and emotions. Specifically, the dorsal hippocampus is involved in cognition as well as learning and memory and the ventral hippocampus in affective brain functions such as anxiety. Therefore, it is easily conceivable that hippocampal neuronal cell death in these areas due to S1 protein administration may lead to the cognitive deficits and anxiety-like behavior observed in our study. Notably, angiotensin-converting enzyme 2 (ACE2) and neuropilin-1, two receptors for S1 protein, are relatively highly expressed in the hippocampus as compared to other brain regions. This may increase the susceptibility of the hippocampus to the S1 protein effects and might explain why hippocampus-dependent neurological and psychological symptoms such as cognitive deficit or anxiety and depression often manifest in COVID-19 patients.

In our effort to elucidate the mechanisms, we found that S1 protein induced non-cell autonomous hippocampal neuronal cell death. The S1 protein exerted hippocampal neurotoxicity via activating glial cells. More specifically, we found that IL-1β expressed by the S1 protein-activated glia contributes to hippocampal neuronal cell death... Previously, the S1 protein of coronavirus was shown to induce inflammatory cytokines by activating NF-B signaling in microglia, and ACE2 and CD147, receptors that interact with S1, are expressed on glial cells. Taking into account these prior studies, our data suggests that the brain-penetrating S1 protein of SARS-CoV-2 can activate hippocampal glial cells to express IL-1β and thereby induce bystander hippocampal neuronal cell death.

In summary, we present evidence that the S1 protein of SARS-CoV-2 introduced into the hippocampus can induce non-cell autonomous hippocampal neuronal death resulting in cognitive deficit and anxiety-like behavior. This novel mechanism may open a new avenue for the treatment of neurological and psychological symptoms of COVID-19 survivors in the future."