Resveratrol induces molecular changes in cholesterol homeostasis in SAMP8 mice cerebellum

Resveratrol (Rsv) is a natural polyphenol with neuroprotective properties that modulates several pathways implicated in Alzheimer's disease (AD). Cholesterol homeostasis is disrupted in AD patients, and this imbalance plays a key role in amyloid precursor protein (APP) processing, β-amyloid aggregation and membrane stability. The effect of Rsv on the cerebellum, an emerging structure in cognitive networks and AD pathology due to its high connectivity with other brain regions, remains largely unexplored. This study aims to characterize the effects of Rsv on the cerebellum of SAMP8 mice, an animal model of AD, at different ages (5- and 7-month-old mice) and to investigate how it act as a neuroprotective polyphenol in this structure via modulation of cholesterol metabolism. Aging caused a significant increase in cerebellar membrane free cholesterol levels, which were reversed by Rsv treatment. HMG-CoA reductase levels were significantly reduced by Rsv treatment in 5-month-old mice, suggesting that this polyphenol modulates cholesterol synthesis. Parameters related to cholesterol trafficking were also modulated, with increased LDL receptor levels, but without affecting ApoE. Mitochondrial electron transport chain complexes were also upregulated by Rsv treatment in 5-month-old animals, without affecting mitochondrial dynamics. Collectively, these data demonstrate-for the first time-that Rsv modulates key aspects of cholesterol metabolism and mitochondrial function in the cerebella of SAMP8 mice.