RRC ID 78425
Author Nakano-Kobayashi A, Canela A, Yoshihara T, Hagiwara M.
Title Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway.
Journal Proc Natl Acad Sci U S A
Abstract Neuroinflammation is a common feature of neurodegenerative disorders such as Alzheimer's disease (AD). Neuroinflammation is induced by dysregulated glial activation, and astrocytes, the most abundant glial cells, become reactive upon neuroinflammatory cytokines released from microglia and actively contribute to neuronal loss. Therefore, blocking reactive astrocyte functions is a viable strategy to manage neurodegenerative disorders. However, factors or therapeutics directly regulating astrocyte subtypes remain unexplored. Here, we identified transcription factor NF-E2-related factor 2 (Nrf2) as a therapeutic target in neurotoxic reactive astrocytes upon neuroinflammation. We found that the absence of Nrf2 promoted the activation of reactive astrocytes in the brain tissue samples obtained from AD model 5xFAD mice, whereas enhanced Nrf2 expression blocked the induction of reactive astrocyte gene expression by counteracting NF-κB subunit p65 recruitment. Neuroinflammatory astrocytes robustly up-regulated genes associated with type I interferon and the antigen-presenting pathway, which were suppressed by Nrf2 pathway activation. Moreover, impaired cognitive behaviors observed in AD mice were rescued upon ALGERNON2 treatment, which potentiated the Nrf2 pathway and reduced the induction of neurotoxic reactive astrocytes. Thus, we highlight the potential of astrocyte-targeting therapy by promoting the Nrf2 pathway signaling for neuroinflammation-triggered neurodegeneration.
Volume 120(33)
Pages e2303809120
Published 2023-8-15
DOI 10.1073/pnas.2303809120
PMID 37549281
PMC PMC10438385
MeSH Alzheimer Disease* / metabolism Animals Astrocytes / metabolism Cognitive Dysfunction* / metabolism Inflammation / metabolism Mice Microglia / metabolism NF-E2-Related Factor 2* / genetics NF-E2-Related Factor 2* / metabolism NF-kappa B / metabolism Neuroinflammatory Diseases
Human and Animal Cells 201B7-Ff(HPS4290)