Early astrocyte-targeted intervention guided by (18)F-SMBT-1 imaging attenuates disease progression in 3xTg-AD mice.

PURPOSE: Astrocyte reactivity is a key pathological feature and potential therapeutic target of Alzheimer's disease (AD), however, the optimal timing of its modulation remains unexplored. This study aims to combine (18)F-SMBT-1 based molecular imaging with astrocyte-targeted intervention in 3xTg-AD mice to address this challenge. METHODS: PET imaging with (18)F-SMBT-1 was conducted in 3xTg-AD mice at 4, 6, 10, and 12 months of age, with age-matched wild-type (WT) mice as controls. The standardized uptake value ratio was calculated using cerebellum as the reference region by PMOD software. Immunofluorescence (IF) analysis was used to assess astrocyte reactivity ex vivo. Astrocyte-targeted intervention via Nrf2 overexpression was performed in 4-month-old 3xTg-AD mice using adeno-associated virus vectors. Following intervention, PET imaging with (18)F-SMBT-1 was performed to assess astrocyte reactivity, open field test and Morris water maze test were performed to evaluate cognitive function, and IF analysis was used to assess pathological feature of AD. RESULTS: In 3xTg-AD mice of different ages, higher uptake of (18)F-SMBT-1 was observed in the cortex and hippocampus compared to age-matched WT controls. IF analysis further confirmed the presence of reactive astrocytes activation in 3xTg-AD mice. Both in vivo (18)F-SMBT-1 imaging and ex vivo IF analysis identified early-onset astrocyte activation in 3xTg-AD mice. Based on these observations, we implemented early astrocyte-targeted intervention via Nrf2 overexpression at 4 months of age in 3xTg-AD mice. Subsequent in vivo (18)F-SMBT-1 PET imaging demonstrated a significant reduction in astrocyte reactivity following this intervention. Our findings also demonstrated that early astrocyte-targeted intervention might delay AD pathological progression in 3xTg-AD mice, as supported by attenuated anxiety-like behavior and ameliorated neuropathological features. CONCLUSION: (18)F-SMBT-1 PET imaging served as a diagnostic biomarker for monitoring astrocyte reactivity to guide therapeutic timing decisions, and as a therapeutic response indicator for evaluating treatment efficacy. Early astrocyte-targeted intervention demonstrated significant therapeutic potential. These findings highlighted the translational potential of molecular imaging-guided strategies and astrocyte-targeted therapies in AD.