Background: Deficits in mitochondrial function and oxidative stress play
pivotal roles in Down syndrome (DS) and Alzheimer’s disease (AD) and these alterations in
mitochondria occur systemically in both conditions.
Objective: We hypothesized that peripheral cells of elder subjects with DS
exhibit disease-specific and dementia-specific metabolic features. To test this, we
performed a comprehensive analysis of energy metabolism in lymphoblastic-cell-lines (LCLs)
derived from subjects belonging to four groups: DS-with-dementia (DSAD),
DS-without-dementia (DS), sporadic AD, and age-matched controls.
Methods: LCLs were studied under regular or minimal feeding regimes with
galactose or glucose as primary carbohydrate sources. We assessed metabolism under
glycolysis or oxidative phosphorylation by quantifying cell viability, oxidative stress,
ATP levels, mitochondrial membrane potential (MMP), mitochondrial calcium uptake, and
autophagy.
Results: DS and DSAD LCLs showed slower growth rates under minimal feeding.
DS LCLs mainly dependent on mitochondrial respiration exhibited significantly slower
growth and higher levels of oxidative stress compared to other groups. While ATP levels
(under mitochondrial inhibitors) and mitochondrial calcium uptake were significantly
reduced in DSAD and AD cells, MMP was decreased in DS, DSAD, and AD LCLs. Finally, DS LCLs
showed markedly reduced levels of the autophagy marker LC3-II, underscoring the close
association between metabolic dysfunction and impaired autophagy in DS.
Conclusion: There are significant mitochondrial functional changes in LCLs
derived from DS, DSAD, and AD patients. Several parameters analyzed were consistently
different between DS, DSAD, and AD lines suggesting that metabolic indicators between LCL
groups may be utilized as biomarkers of disease progression and/or treatment outcomes.
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