Affiliations: [a] Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| [b] Department of Pharmacology & Toxicology, The University of Kansas, Lawrence, KS, USA
| [c] Higuchi Biosciences Center, The University of Kansas, Lawrence, KS, USA
| [d] Health Management Center, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| [e] Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
Correspondence:
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Correspondence to: Lan Guo, MD, PhD, Assistant Research Professor, Higuchi Biosciences Center, The University of Kansas, Lawrence, KS 66045, USA. Tel.: +1 785 864 4002; E-mail: lan.guo@ku.edu.
Abstract: 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.
