In recent years, caloric overconsumption derived mostly from saturated fat has contributed to the global obesity pandemic and the development of metabolic and brain disorders. Growing evidence in humans and mouse models suggests that the consumption of a high-fat diet increases the risk of Alzheimer’s disease and other forms of cognitive impairment. But how high-fat diets exert adverse effects on the human brain and contribute to the development of Alzheimer’s remain largely unknown.

Sarroca and colleagues from the Institut d’Investigacions Biomèdiques de Barcelonssa in Spain assessed the triggering and progression of Alzheimer’s disease pathology induced by a high-fat diet and the effects of resveratrol, a polyphenol found in common dietary sources with neuroprotective activities. In their article published in The Journal of Nutritional Biochemistry, resveratrol protected against high-fat diet-induced memory loss in mice and prevented memory loss in genetically modified mice that model Alzheimer’s disease. Resveratrol also reduced the manifestation of the hallmarks of Alzheimer’s disease—amyloid plaques and neurofibrillary tangles.

These results add further support to the proposed benefits of resveratrol as a nutraceutical agent against neurodegeneration and Alzheimer’s disease. “Our data suggest that resveratrol can correct the harmful effects of a high-fat diet on the brain and may be a potential therapeutic agent against obesity-related disorders and Alzheimer’s disease pathology,” said the authors in their article.

(Sarroca 2020 | J Nutr Biochem) The effects caused by a high-fat diet and resveratrol in healthy and Alzheimer’s disease mice. During the 16 weeks of the treatment, a high-fat diet (HFD) increased mouse body weight, decreased glucose tolerance, and activated pathways for generating amyloid plaques and tau neurofibrillary tangles in both healthy and Alzheimer’s disease (5XFAD) mice. Resveratrol jointly with HFD reduced the exacerbated amyloid depositions in the brain of 5XFAD mice and reduced the amyloidogenic pathway and tau pathology in both strains. Notably, administration of resveratrol protected against high fat diet-induced cognitive impairment and behavioral alterations.

Diets as a determinant of dementia

Diet is an important determinant of healthy brain aging since excessive consumption of calories from high-fat diets is linked to an increased risk of developing Alzheimer’s. Experimental studies have shown that a diet highly enriched in lard induces obesity, inflammation, oxidative stress, and Alzheimer’s disease-like changes in the brain. These effects are mainly attributed to saturated fats, although moderate cholesterol content can also contribute. However, how these processes occur is still poorly understood and, importantly, how to therapeutically intervene.

Mimicking calorie restriction with resveratrol

Resveratrol is a polyphenol found in common dietary sources such as grapes and berries. It exhibits a wide spectrum of potential therapeutic activities, including antioxidant, anti-inflammatory, neuroprotective, and longevity-promoting properties. In fact, resveratrol mimics the beneficial effects of dietary caloric restriction, one of the most effective mechanisms for extending the lifespan and delaying age-related diseases in experimental animals. Although resveratrol is also able to attenuate the deleterious effects in high fat diet-fed mice and improve memory deficits, how it does so is not fully understood.

In the present study, Sarroca and colleagues analyzed the molecular pathways involved in the progression of Alzheimer’s disease development as a result of high-fat diet-induced metabolic stress. Over 16 weeks, healthy and Alzheimer’s transgenic 5XFAD mice were fed a control diet, high fat diet, or high-fat diet supplemented with 0.1% resveratrol. This dose of resveratrol was previously shown to protect against Alzheimer’s disease development in another mouse model of the neurodegenerative disease (3xTg-AD) and to induce cognitive enhancement in healthy mice, both fed a typical, non-high fat diet.

A high-fat diet triggers Alzheimer’s disease hallmarks in mice

Sarroca and colleagues demonstrated that in both the healthy and Alzheimer’s disease mice that the high-fat diet-induced behavioral and psychological symptoms of dementia, including anxiety and neophobia—extreme or irrational fear or dislike of anything new or unfamiliar. Also, the high-fat diet worsened memory function in healthy mice.

A high-fat diet induces behavioral and psychological symptoms of dementia

The study demonstrated that a high-fat diet aggravates amyloid pathology in the 5XFAD mouse model, with increases in amyloid burden in brain areas critical to learning and memory including the cerebral cortex, amygdala, and hippocampus. The high-fat diet also aggravated tau pathology in both healthy and Alzheimer’s disease mice, with the increase in pTau shown in the cerebral cortex.

Resveratrol recovers behavior and memory loss in mice fed a high-fat diet

Interestingly, the brains of these mice showed that resveratrol was able to fight these harmful effects of a high-fat diet. Resveratrol normalized changes in behavioral and psychological symptoms of dementia in both strains. It also preserved memory capacity in healthy mice and induced complete protection against memory loss in mice modeling Alzheimer’s disease.

(Sarroca 2020 | J Nutr Biochem) Fig. 2. The neuroprotective effects of resveratrol on cognition. Healthy (WT) and Alzheimer’s disease (5XFAD) mice were tested for their ability to recognize objects, a memory test. The performance of both healthy and Alzheimer’s disease mice in object recognition was negatively affected by a high-fat diet, which was recovered by supplementation with resveratrol (RV).

Resveratrol protects against pathological mechanisms induced by a high-fat diet

In terms of how this was happening, the study demonstrated that a high-fat diet aggravates amyloid pathology in the 5XFAD mouse model, with increases in amyloid burden in the cerebral cortex, amygdala, and subiculum; it also aggravated tau pathology in both WT and 5XFAD mice, with the increase in pTau shown in the cerebral cortex. Interestingly, analysis of brain pathological changes showed that resveratrol was able to fight these harmful effects of HFD.

(Sarroca 2020 | J Nutr Biochem) Resveratrol is neuroprotective in the high fat diet-fed and Alzheimer’s mice. Mice were evaluated for levels of a fragment from amyloid precursor protein (APP-CTF) (B, left) and the formation of amyloid plaques (D, right), which are diagnostic biomarkers for Alzheimer’s disease. A high-fat diet increased the levels of APP-CTF in Alzheimer’s disease (5XFAD) mice, which was ameliorated by resveratrol (RV) supplementation. Resveratrol decreased fibrillar amyloid plaques in the amygdala and subiculum brain regions of high-fat diet Alzheimer’s disease mice, and to a lesser extent in the cingulate cortex, correlating with downregulated APP-CTF levels. These results show that resveratrol mitigates amyloid pathology.

Resveratrol as a therapeutic option for neurodegeneration and Alzheimer’s disease

The findings support the contention that dietary factors may increase the risk of Alzheimer’s disease or worsen its progression. The neuroprotective nutraceutical resveratrol counteracts the deleterious effects of the diet by reducing amyloid and tau pathologies, aiding the recovery of memory skills, and reducing anxiety and neophobia. These results add further support to the proposed benefits of resveratrol as a nutraceutical agent against neurodegeneration and Alzheimer’s disease.