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Basic Science and Pathogenesis
Thi Kim Oanh Nguyen1, Sergey A Trushin1, Mark Ostroot1
1Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
Mild inhibition of mitochondrial complex I (mtCI) with CP2 enhances glucose metabolism and brain energy homeostasis, offering a potential new therapeutic strategy for Alzheimer's disease (AD). This approach shows promise for delaying AD onset and progression.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Alzheimer's disease (AD) necessitates novel treatments beyond amyloid-beta (Aβ) targeting.
- Mitochondrial dysfunction and impaired brain energy homeostasis are early AD hallmarks.
- Mitochondrial complex I (mtCI) inhibition is a potential therapeutic strategy.
Purpose of the Study:
- To elucidate the mechanistic link between mtCI inhibition, glucose metabolism, and energy homeostasis in AD.
- To assess the impact of mtCI inhibition on cellular energy metabolism in AD models.
Main Methods:
- Assessed cellular energy metabolism in APPswe-expressing neuroblastoma cells and controls using Seahorse Analyzer.
- Measured glycolytic function, mitochondrial energetics, fatty acid β-oxidation (FAO), and glucose uptake.
- Analyzed GLUT translocation, protein expression, and specific metabolites via flow cytometry, Western blot, and mass spectrometry.
Main Results:
- APPswe cells showed reduced glycolysis and respiratory capacity, with partial compensation by FAO.
- CP2 treatment acutely enhanced glucose transporter (GLUT) translocation and glucose uptake.
- CP2 facilitated glucose utilization in oxidative phosphorylation (OXPHOS) via AMPK, enhancing TCA cycle function.
Conclusions:
- Mild mtCI inhibition activates neuroprotective mechanisms, including improved glucose metabolism and energy homeostasis.
- CP2 demonstrates therapeutic potential for Alzheimer's disease by addressing energy deficits.
- Findings in human cells and AD mouse models support the translational viability of this approach.
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