Folic Acid Plus α-Tocopherol Mitigates Amyloid-β-Induced Neurotoxicity through Modulation of Mitochondrial Complex Activity

Early symptoms of Alzheimer's disease (AD) have been attributed to amyloid-beta (A beta) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective A beta protein metabolism, neuroinflammation, oxidative processes, and mitochondrial dysfunction. In the current study, we assessed the molecular mechanisms, mainly the modifications in the activity of mitochondrial complexes, whereby the association of folic acid and alpha-tocopherol protects mice against the A beta-induced neurotoxicity. Oral treatment with folic acid (50 mg/kg) plus alpha-tocopherol (500 mg/kg), once a day during 14 consecutive days, protected mice against the A beta(1-40)-induced cognitive decline, synaptic loss, and neuronal death. However, chronic treatment comprising folic acid plus alpha-tocopherol was ineffective on A beta-induced glial cell activation, suggesting that the effect of this treatment is independent of anti-inflammatory features. Interestingly, the results obtained in our study suggest that mitochondrial energy metabolism is impaired by the A beta peptide, and upregulation of mitochondrial genes may be a compensatory response, as demonstrated by the increase in mitochondrial complexes I, II, and IV activity, in the hippocampus of mice, after A beta(1-40) injection. Of note, the chronic treatment comprising folic acid plus alpha-tocopherol prevented the increase in the activity of mitochondrial complexes I and IV induced by A beta(1-40). Together, these results show the antioxidant effect of the combination of folic acid and alpha-tocopherol, as observed by the decrease in NO generation from iNOS and nNOS, preventing an increase in the activity of mitochondrial complexes, mainly I and IV, and the neuronal death induced by the A beta(1-40) peptide.