Obesity has been associated with neurodegeneration and cognitive dysfunctions. Recent data showed that pistachio consumption is able to prevent and ameliorate dyslipidemia, hepatic steatosis, systemic and adipose tissue inflammation in mice fed a high-fat diet (HFD). The present study investigated the neuroprotective effects of pistachio intake in HFD mice. Three groups of mice were fed a standard diet (STD), HFD, or HFD supplemented with pistachio (HFD-P) for 16 weeks. Metabolic parameters (oxidative stress, apoptosis, and mitochondrial dysfunction) were analyzed by using specific assays and biomarkers. The pistachio diet significantly reduced the serum levels of triglycerides and cholesterol in the HFD model. No difference was observed in the index of insulin resistance between HFD and HFD-P. A higher number of fragmented nuclei were found in HFD cerebral cortex compared to STD and HFD-P. A decrease in reactive oxygen species, singlet oxygen and phosphorylated extracellular signal-regulated kinase, and an increase of superoxide dismutase 2 and heme oxygenase expression were found in the brains of the HFD-P samples compared to HFD. Furthermore, the impaired mitochondrial function found in HFD brain was partially recovered in HFD-P mice. These results suggest that the regular intake of pistachio may be useful in preventing obesity-related neurodegeneration, being able to reduce both metabolic and cellular dysfunctions.The positive effects of the Mediterranean diet on health have been well documented [9,10]. The longevity of one Mediterranean population, over 90 years old without dementia, was attributed to the nutraceutical components of the Mediterranean diet [11]. Functional food has been reported to delay or inhibit neurodegeneration, suggesting their employment as an alternative therapeutic strategy for correlated diseases [12][13][14].Benefits of nut consumption (mainly pistachios, walnuts, and almonds) have been described in studies on both animals and humans [15,16]. Daily nut consumption can improve dysmetabolic conditions such as obesity, type 2 diabetes, and related cardiovascular diseases [17,18]. In particular, Pistacia atlantica oleoresin has been proposed as an agent that protects the body against conditions associated with oxidative stress [19], including memory impairment, in lipopolysaccharide-treated rats [20]. Nevertheless, the potential beneficial impact of nut intake on neurodegenerative disorders, as well as on other cognitive-behavioral deficits, has been poorly explored.Compared to other nuts, pistachios possess a healthier nutritional profile, with low-fat content, high content of polyunsaturated fatty acids (13.3 g/100 g) and mono-unsaturated fatty acids (24.5 g/100 g), minerals (potassium, phosphorus, magnesium, and calcium) and vitamins (vitamin A, vitamin E, vitamin C, and vitamins B). Phytochemicals of pistachio show high bioavailability, contributing to the beneficial relationship between pistachio consumption and health-related outcomes [21]. Furthermore, recent data have demonstra...