Folic Acid Plus α-Tocopherol Mitigates Amyloid-β-Induced Neurotoxicity through Modulation of Mitochondrial Complexes Activity¹

Article type: Research Article

Authors: Figueiredo, Cláudia P.^{a; b} | Bicca, Maíra A.^a | Latini, Alexandra^{b; c} | Prediger, Rui Daniel S.^{a; b} | Medeiros, Rodrigo^a | Calixto, João B.^{a; *}

Affiliations: [a] Departamento de Farmacologia, Centro de ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil | [b] Programa de Pós-Graduação em Neurociências, Centro de ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil | [c] Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil

Correspondence: [*] J.B. Calixto, Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco D, CCB, Caixa Postal 476, CEP 88049-900, Florianópolis, Santa Catarina, Brazil. Tel.: +55 48 3721 9491; Fax: +55 48 3337 5479; E-mail: [email protected], [email protected].

Note: [1] This article received a correction notice (Erratum) with the reference: 10.3233/JAD-229023, available at http://doi.org/10.3233/JAD-229023.

Abstract: Early symptoms of Alzheimer’s disease (AD) have been attributed to amyloid-β (Aβ) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective Aβ 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 a-tocopherol protects mice against the Aβ-induced neurotoxicity. Oral treatment with folic acid (50 mg/kg) plus a-tocopherol (500 mg/kg), once a day during 14 consecutive days, protected mice against the Aβ1–40-induced cognitive decline, synaptic loss, and neuronal death. However, chronic treatment comprising folic acid plus a-tocopherol was ineffective on Aβ-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 Aβ 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 Aβ1–40 injection. Of note, the chronic treatment comprising folic acid plus a-tocopherol prevented the increase in the activity of mitochondrial complexes I and IV induced by Aβ1–40. Together, these results show the antioxidant effect of the combination of folic acid and a-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 Aβ1–40 peptide.

Keywords: Alpha-tocopherol, amyloid-β, cognition, folic acid, mitochondrial complexes

DOI: 10.3233/JAD-2010-101320

Journal: Journal of Alzheimer's Disease, vol. 24, no. 1, pp. 61-75, 2011