Prodromal Metabolic Phenotype in MCI Cybrids: Implications for Alzheimer’s Disease
Abstract
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.
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MCI cybrid lines generated through transfer of MCI platelet mitochondria to mtDNA-depleted cells showed low mean COX activity and other downstream molecular changes.
“Two studies in which “MCI cybrid” lines were generated through transfer of MCI platelet mitochondria to mtDNA-depleted cells observed low mean COX activity and other downstream molecular changes [92, 93].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [92]
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“[36] Silva DF, Santana I, Esteves AR, Baldeiras I, Arduino DM, Oliveira CR, Cardoso SM.”
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- Authors
- F. Silva, D., Santana, I., R. Esteves, A., Baldeiras, I., M. Arduino, D., R. Oliveira, C., & M. Cardoso, S.
- Venue
- Current Alzheimer Research
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2013-02-01
- Volume
- 10
- Issue
- 2
- Pages
- 180-190
- ISSN
- 1567-2050 (ISSN-L)
- OpenAlex
- W2062120655
- Cited by
- 33
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 3 · 2022: 1 · 2021: 5 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 4 · 2016: 1 · 2015: 1 · 2014: 6 · 2013: 4
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Alzheimer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- mild cognitive impairment, Alzheimer's disease, cybrids, mitochondrial dysfunction, mitochondrial DNA, oxidative damage, lipid peroxidation, superoxide, protein carbonyls, cytochrome c oxidase, mitochondrial membrane potential, amyloid-beta oligomers, NT2 cells, platelets
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Animals, Blood Platelets, Citrate (si)-Synthase, Electron Transport Complex IV, DNA, Mitochondrial, Female, Humans, Hybrid Cells, Microscopy, Electron, Superoxides, Case-Control Studies, Amyloid beta-Peptides, Thiobarbituric Acid Reactive Substances, Teratocarcinoma, Cell Line, Tumor, Protein Carbonylation, Membrane Potential, Mitochondrial, Cognitive Dysfunction
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