👤 Christian Griñán-Ferré

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. Show less

Cholesterol metabolism seems dysregulated and linked to amyloid-β (Aβ) formation in neurodegeneration, but the underlying mechanisms are poorly known. Resveratrol (RSV) is a polyphenol with antioxidant activity and neuroprotective properties. Here, we analyzed the effect of age and RSV supplementation on cholesterol metabolism in the brain and blood serum, and its potential link to Aβ processing, in SAMP8 mice-an animal model of aging and Alzheimer's disease. In the brain, our results revealed an age-related increase in ApoE and unesterified cholesterol in the plasma membrane whereas LDL receptor, HMG-CoA reductase, HMG-CoA-C1 synthase, and ABCA1 transporter remained unaltered. Furthermore, BACE-1 and APP gene expression was decreased. This dysregulation could be involved in the amyloidogenic processing pathway of APP towards Aβ formation. In turn, RSV exhibited an age-dependent effect. While levels of unesterified cholesterol in the plasma membrane were not affected by RSV, several participants in cholesterol uptake, release, and de novo synthesis differed, depending on age. Thus, RSV supplementation exhibited a different neuroprotective effect acting on Aβ processing or cholesterol metabolism in the brain at earlier or later ages, respectively. In blood serum, HDL lipoprotein and free cholesterol were increased by age, whereas VLDL and LDL lipoproteins remained unaltered. Again, the protective effect of RSV by decreasing the LDL or increasing the HDL levels also seems to depend on the intervention's moment. In conclusion, age is a prominent factor for cholesterol metabolism dysregulation in the brain of SAMP8 mice and influences the protective effects of RSV through cholesterol metabolism and Aβ processing. Show less