SARS-CoV-2 Spike protein induces cellular senescence and cognitive vulnerability to amyloid-β oligomers

Cognitive impairment is often reported in post-COVID-19 syndrome, and evidence suggests that the Spike protein is released during SARS-CoV-2 infection, even without the presence of viral RNA. Cellular senescence is a process in which cells lose the ability to divide and undergo functional changes. The senescence-associated secretory phenotype (SASP) is a phenomenon present in several neuroinflammatory conditions that include cognitive impairment, such as Alzheimer's disease. In this study, we investigated whether Spike-induced senescence creates a persistent neurological vulnerability. Using murine models, we observed that Spike exposure increased SASP-related gene expression (TNF-α, TGF-β, IL-1β), DNA damage markers (53BP1, γ-H2AX), and the senescence indicator p16INK4a in the brain. Spike exposure induced memory deficits between 30 and 45 days, which spontaneously resolved by 60 days. To determine if this apparent behavioral recovery masked a latent biological susceptibility, 60-day recovered mice received an intracerebroventricular infusion of amyloid-β oligomers (AβOs) at a sub-toxic dose (1 pmol). While harmless to control animals, this AβO dose triggered cognitive impairment in Spike-exposed mice during the novel object recognition task, revealing a persistent vulnerability to secondary insults. Crucially, oral treatment with the senolytics Dasatinib (5 mg/kg) and Quercetin (50 mg/kg) prevented both the initial Spike-induced memory deficit and the subsequent AβO-triggered impairment. These findings suggest that behavioral recovery following Spike exposure does not imply complete physiological resolution, suggesting that senescence-related processes may represent a link between prior neuroinflammatory challenge and increased susceptibility to subsequent cognitive dysfunction. Senolytic therapies may offer a promising strategy to mitigate these long-term neurological risks.

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Cell Rep. (2023) 42:112189.

Nat. Aging (2023) 3:1561.