Astrocyte‐Specific Nrf2 Expression Transforms Neurotoxic Reactive Astrocytes to Neuroprotective Phenotype in 3xTg‐AD Mice

ABSTRACT Astrocyte reactivity is a common feature of Alzheimer's disease (AD), with reactive astrocytes traditionally subdivided into neurotoxic or neuroprotective phenotypes. It's crucial to transform neurotoxic reactive astrocytes to neuroprotective phenotypes for the treatment of AD, particularly during the progression of the disease. In this study, we evaluated the role of nuclear factor E2‐related factor 2 (Nrf2) in facilitating the phenotype transformation of reactive astrocytes in vivo and in vitro by overexpressing Nrf2 in hippocampal astrocytes of 3xTg‐AD mice using adeno‐associated virus (AAV) vectors, as well as treating neurotoxic reactive astrocytes with dimethyl fumarate (a Nrf2 activator). We also evaluated the therapeutic effect of astrocyte‐specific Nrf2 in 3xTg‐AD mice with coexpression of Aβ and tau pathologies. Our findings indicate that Nrf2 could facilitate the conversion of neurotoxic reactive astrocytes to neuroprotective phenotypes in vivo and in vitro. AAV‐mediated astrocyte‐specific Nrf2 expression improved cognitive function, reduced Aβ and tau pathologies, rescued the loss of neurons and synapses, and ameliorated neuroinflammation in 3xTg‐AD mice. These findings highlighted the role of Nrf2 in modulating reactive astrocyte phenotypes and suggested the potential for utilizing AAV to target astrocyte‐specific Nrf2 as a promising therapeutic strategy for AD.