Lymphocytic Mitochondrial Aconitase Activity is Reduced in Alzheimer's Disease and Mild Cognitive Impairment

Article type: Research Article

Authors: Mangialasche, Francesca^{a; b} | Baglioni, Mauro^a | Cecchetti, Roberta^a | Kivipelto, Miia^b | Ruggiero, Carmelinda^a | Piobbico, Danilo^c | Kussmaul, Lothar^d | Monastero, Roberto^e | Brancorsini, Stefano^{c; *} | Mecocci, Patrizia^{a; *}

Affiliations: [a] Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy | [b] Aging Research Center, Karolinska Institutet-Stockholm University, Stockholm, Sweden | [c] Department of Experimental Medicine - Section of Terni, University of Perugia, Italy | [d] Department of Central Nervous System Research, Boehringer-Ingelheim Pharma GmbH & Co, Biberach an der Riss, Germany | [e] Section of Neurology, Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy

Correspondence: [*] Correspondence to: Stefano Brancorsini, PhD, Department of Experimental Medicine – Section of Terni, University of Perugia, Via Mazzieri, 3, 05100 Terni, Italy. Tel.: +39 0744 202820; Fax: +39 0744 202804; E-mail: [email protected] and Patrizia Mecocci, MD PhD, Section of Gerontology and Geriatrics, University of Perugia, Ospedale S. Maria della Misericordia Perugia, Block C Floor 4, S.Andrea delle Fratte, 06156 Perugia, Italy. Tel.: +39 075 578 3270; Fax: +39 075 578 3878; E-mail: [email protected].

Abstract: Background:Specific mechanisms behind the role of oxidative/nitrosative stress and mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis remain elusive. Mitochondrial aconitase (ACO2) is a Krebs cycle enzyme sensitive to free radical-mediated damage. Objective:We assessed activity and expression of ACO2 extracted from blood lymphocytes of subjects with AD, mild cognitive impairment (MCI), older adults with normal cognition (OCN, age ≥65 years), and younger adults with normal cognition (YCN, age <65 years). Plasma levels and activities of antioxidants were also measured. Methods:Blood samples were collected from 28 subjects with AD, 22 with MCI, 21 OCN, and 19 YCN. ACO2 activity was evaluated in a subsample before and after in vitro exposure to free radicals. Results:ACO2 activity was significantly lower in AD and MCI cases than controls: ACO2 median activity was 0.64 ± 0.21 U/mg protein for AD, 0.93 ± 0.28 U/mg protein for MCI, 1.17 ± 0.78 U/mg protein for OCN subjects, and 1.23 ± 0.43 U/mg protein for YCN individuals. In subjects with AD and MCI, ACO2 expression was lower than OCN subjects, and ACO2 activity correlated with vitamin E plasma levels (rho: 0.64, p < 0.001) and Mini-Mental State Examination total score (rho: 0.82, p < 0.001). Furthermore, free radicals exposure reduced ACO2 activity more in individuals with AD than in OCN subjects. Conclusion:Our results suggest that ACO2 activity is reduced in peripheral lymphocytes of subjects with AD and MCI and correlates with antioxidant protection. Further studies are warranted to verify the role of ACO2 in AD pathogenesis and its importance as a marker of AD progression.

Keywords: Aconitase (aconitate hydratase), Alzheimer disease, antioxidants, free radicals, lymphocyte, mild cognitive impairment, mitochondria, oxidative stress, reactive nitrogen species, reactive oxygen species

DOI: 10.3233/JAD-142052

Journal: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 649-660, 2015