Triheptanoin Mitigates Brain ATP Depletion and Mitochondrial Dysfunction in a Mouse Model of Alzheimer’s Disease
Pascual, Juan M.
Scholarly/refereed, author accepted manuscript
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Background: Brain energy failure is an early pathological event associated with synaptic dysfunction in Alzheimer’s disease (AD). Thus, mitigation or enhancement of brain energy metabolism may offer a therapeutic avenue. However, there is uncertainty as to what metabolic process(es) may be more appropriate to support or augment since metabolism is a multiform process such that each of the various metabolic precursors available is utilized via a specific metabolic pathway. In the brain, these pathways sustain not only a robust rate of energy production but also of carbon replenishment. Objective: Triheptanoin, an edible odd-chain fatty acid triglyceride, is uncommon in that it replenishes metabolites in the tricarboxylic acid cycle (TCA) cycle via anaplerosis in addition to fueling the cycle via oxidation, thus potentially leading to both carbon replenishment and enhanced mitochondrial ATP production. Methods: To test the hypothesis that triheptanoin is protective in AD, we supplied mice with severe brain amyloidosis (5×FAD mice) with dietary triheptanoin for four and a half months, followed by biological and biochemical experiments to examine mice metabolic as well as synaptic function. Results: Triheptanoin treatment had minimal impact on systemic metabolism and brain amyloidosis as well as tauopathy while attenuating brain ATP deficiency and mitochondrial dysfunction including respiration and redox balance in 5×FAD mice. Synaptic density, a disease hallmark, was also preserved in hippocampus and neocortex despite profound amyloid deposition. None of these effects took place in treated control mice. Conclusion: These findings support the energy failure hypothesis of AD and justify investigating the mechanisms in greater depth with ultimate therapeutic intent.
Yuan, X., Wang, L., Tandon, N., Sun, H., Tian, J., Du, H., Pascual, J. M., & Guo, L. (2020). Triheptanoin Mitigates Brain ATP Depletion and Mitochondrial Dysfunction in a Mouse Model of Alzheimer's Disease. Journal of Alzheimer's disease : JAD, 78(1), 425–437. https://doi.org/10.3233/JAD-200594
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