WO2025078851A8 - Methods of treating cognitive deficit - Google Patents

Abstract

Here, the Inventors show that chronic IL- 1 -induced H2A.X signaling, which mediated DNA DSB response, in hippocampal neurons is a critical driver of cognitive deficits in chronic low grade neuroinflammation. They show that mice chronically infected with the brain- persisting T. gondii parasite display deficits in spatial memory consolidation without general memory loss. Extensive mapping of the neuroinflammatory landscape, beyond a latent T. gondii infection elicited type 1-like neuroinflammation, display elevated production of IL-1α and IL-1β in the hippocampus. Using a mouse model to specifically delete the IL-1 receptor from excitatory neurons, they uncovered that neuronal IL-1 signaling is required for the spatial memory deficits caused by latent T. gondii infection. By singling out a chronic exposure to IL- ip they found that IL-1β signaling in neurons indeed impairs spatial memory. Moreover, they showed that chronic exposure to IL-1β increases DNA DSB levels in neurons, and that neuronal H2A.X-dependent DSB response mediates the IL-1β-induced memory deficits. Importantly, neuronal DSBs were also increased upon T. gondii infection and the deficit in hippocampus- dependent spatial memory caused by T. gondii infection was prevented by the abrogation of neuronal H2A.Xdependent signaling. These results highlight the instrumental role of cytokine- induced DSB-dependent signaling in spatial memory defects elicited by a chronic infectious neuroinflammatory process. Accordingly, the present invention relates to a method of treating a subject suffering from cognitive deficit comprising administering to said subject a therapeutically effective amount of an inhibitor of IL- 1 -induced H2A.X signaling.