Neuroprotective mechanisms of resveratrol in a high-fat diet-fed Alzheimer's disease mouse model

Over the last decades there has been an over consumption of foods rich in animal fats that has led to a global obesity pandemic. Obesity presents itself with a number of comorbidities, including an increased risk for the development of neurodegenerative disorders such as Alzheimer’s disease (AD). On the other hand, reducing caloric intake has showed to delay age-related diseases and resveratrol, a polyphenol produced by a variety of plants, has emerged as a potent mimetic of this caloric restriction. The mechanisms underlying both effects are not fully understood and, as potential therapeutic targets, need to be thoroughly analyzed. To this end, we have analyzed molecular pathways involved in memory loss in mice as a result of a high-fat diet (HFD) administration and the role that resveratrol supplementation on this diet may play. We have focused on 6-months-old 5xFAD mice, which are transgenic AD mice with a high amyloid burden, and wild type (WT) mice. Both mice strains fed with HFD showed impairment of recognition memory but when resveratrol was added to the HFD, recognition memory was restored. Moreover, our results indicate that HFD boosts amyloid pathology in both, WT and 5xFAD mice, mainly through the potentiation of the amyloidogenic pathway and the reduction of the non-amyloidogenic one. Namely, we identified an increase in β-secretase (BACE1) protein levels in both strains and a decrease in α-secretase (ADAM10) expression in WT mice after HFD administration. Tau pathology was as well aggravated in both strains. Interestingly, HFD has showed the capacity to enhance the activity of the ubiquitin-proteasome system, being the most significant changes the induction of proteasome caspase-like and chymotrypsin-like activities. Remarkably, resveratrol has demonstrated the capability to normalize all the pathological changes induced by the HFD in both WT and 5xFAD mice, confirming its preventive and therapeutic potential against neurodegeneration.SAF2016-77703-C2-2-R of the Ministerio de Economía y Competitividad, Spain and the European Regional Development Fund (ERDF); AGAUR 2017-SGR-106 and the CERCA Programme of the Generalitat de Catalunya; R. Copas and C. Sanfeliu belong to Group 05 of CIBER Epidemiología y Salud Pública (CIBERESP) of the Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, SpainPeer reviewe