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Mitochondrial dysfunction, oxidative stress, inflammation and glucose dysmetabolism are pathological signs of Alzheimer's disease (AD). Dietary aluminum (Al) overload is often used to induce AD in rodents and trigger the onset of oxidative-stress hallmarks resembling those of the human disease. The Nuclear factor erythroid 2–related factor 2 (Nrf2), owing to its key role in redox homeostasis, mitochondrial function and inflammation, is a promising drug target for neurological disorders, but only a few data are available on its modulatory effects on glucose transporter expression levels. While it has been found that the protective effect of Conjugated linoleic acid (CLA) occurs through the activation of an Nrf2-mediated adaptive response, its beneficial effect on the considered pathological signs in the Al -induced model has not been established yet. Thirty-five male BalbC mice were divided into 5 groups: two Al -intoxicated groups were treated for 5 weeks with low or high Al doses (8 or 100 mg/kg/day in drinking water, respectively; L or H). Two groups of animals, orally supplemented with CLA (600 mg/kg bw/day) for 7 weeks (2 preliminary weeks plus the 5-week treatment with Al ; CLA + L , CLA + H) were used to investigate its protective effect, while untreated mice were used as control (Cntr). We provide evidence that mitochondrial dysfunction, Nrf2 alteration, inflammation and Acetylcholinesterase (AChE) hyperactivation can occur even from L exposure. Interestingly, animal pre-treatment with an allometric CLA dose led to significant downregulation of the toxic effects elicited by L or H , likely through the activation of an adaptive response. In conclusion, CLA ability to increase the level of glucose transporters - along with its antioxidant and anti-inflammatory effect - expands the therapeutic targets of these molecules and comes out as an intriguing suitable candidate for the treatment of multifactorial disease. The toxic effect triggered by AlCl 3 intake is accompanied by the appearance of some pathognomonic signs of Alzheimer's disease (AD), namely mitochondrial dysfunction, oxidative stress, increased pro-inflammatory cytokines levels, neuronal loss, phase 2 enzyme and acetylcholinesterase (AChE) hyperactivation. Animal supplementation with Conjugated linoleic Acid (CLA) before AlCl 3 treatment activated an Nrf2-mediated adaptive response which restores/prevents the alteration elicited by AlCl 3 intake and upregulates glucose transporters levels (GLUT-1-3,4). [Display omitted] [ABSTRACT FROM AUTHOR]