J Alzheimers Dis. 2025 Aug 13. 13872877251362889
BackgroundIn the past decade, Alzheimer's disease (AD) researchers have found that the formation of amyloid aggregates occurs after dysregulation of respiratory chain activity.ObjectiveUsing our developing mathematical model to identify potential therapeutic targets for AD treatment.MethodsWe have constructed a mathematical model for AD that incorporates enzyme activities and kinetics, and protein and mRNA expression levels.ResultsOur analyses of gene expression in AD brains provide complimentary evidence that changes in mitochondrial energy production and biogenesis accompany AD pathogenesis. Using this data, we created a mitochondrial model of electron transport chain supercomplex assembly.ConclusionsBy carrying out sensitivity analyses of responses to oxidative stress and effects of gene expression on energy production, we demonstrate how oxidative stress and energy deficits change the initial antioxidant defense system and impact the progression of AD. We investigated the impact of gene expression changes in 9 genes as new therapeutic options via metabolic flux analysis of supercomplex assembly. Through careful analysis, we propose that UQCRC1 may be an effective therapy option for in vitro AD treatment testing.
Keywords: Alzheimer's disease; UQCRC1; electron transport chain; gene expression changes; mathematical model; mitochondrial supercomplexes; respirasome