Prodromal Metabolic Phenotype in MCI Cybrids: Implications for Alzheimer’s Disease
D. F. Silva, I. Santana, A. R. Esteves, I. Baldeiras, D. M. Arduino, C. R. Oliveira and S. M. Cardoso
Affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal. 3004-517 Coimbra, Portugal.
Mild cognitive impairment (MCI) is considered a nosological entity or a translational state between normal aging
and sporadic Alzheimer´s disease (AD). From brain tissue to peripheral blood samples, it is evident that the early
markers of metabolic dysfunction observed in AD have also been found in MCI subjects. These observations obtained
from MCI and AD subjects leave open the possibility that mitochondrial dysfunction-induced oxidative damage happening
a priori of symptom onset, may trigger other pathological hallmarks, namely Aβ oligomerization.
In this study, we used a citoplasmic hybrid (cybrid) model created by the repopulation of human teratocarcinoma (NT2)
cells depleted of endogenous mitochondrial DNA (mtDNA) with platelets from age-matched controls, MCI and AD subjects.
We found mitochondrial deficits in MCI and AD cybrids as compared with controls, such as a decrease in cytochrome
c oxidase (COX) activity, a decrease in mitochondrial membrane potential and in mitochondrial cytochrome c
content. Consequently, we analyzed parameters of oxidative damage and found that AD and MCI cybrids exhibit an increase
in lipid peroxides, higher production of superoxide radicals, and higher content in protein carbonyls. Since our data
clearly show alterations in mitochondrial-mediated oxidative damage in MCI cybrids we propose that mitochondrial dysfunction
is an early event in idiopathic AD. Moreover, we found that mitochondrial Aβ oligomeric content increases in
AD, which may exacerbate initial mitochondrial damage. Altogether, our data strongly supports a key role for mitochondria/
mtDNA in aged-driven AD pathology.
Keywords: MCI cybrids, mitochondrial dysfunction, oxidative stress
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