Triheptanoin Supplementation to Ketogenic Diet Curbs Cognitive Impairment in APP/PS1 Mice Used as a Model of Familial Alzheimer’s Disease

Abstract

Diets containing a high proportion of fat with respect to protein plus carbohydrates are capable of inducing ketone body production in the liver, which provides an energetic alternative to glucose. Some ketogenic diets have been tested as therapeutic strategies for treating metabolic disorders related to a deficiency in glucose-driven ATP generation. However, ketone bodies are not capable of providing extra tricarboxylic acid cycle intermediates, limiting the anabolic capacity of the cell. Therefore, it is reasonable to hypothesize that supplementing a ketogenic diet with anaplerotic compounds such as triheptanoin may improve ketogenic diet effectiveness. The present study tests this hypothesis in APP/PS1 (APPswe/PS1dE9) transgenic mice, used as a model of familial Alzheimer's disease because impaired energy supply to neurons has been linked to this neurodegenerative process. Triheptanoin supplementation to a ketogenic diet for three months and starting at the age of three months reduces the memory impairment of APP/PS1 mice at the age of 6 months. The Aβ production and deposition were not significantly altered by the ketogenic diet, supplemented or not by triheptanoin. However, mice fed with triheptanoin-rich ketogenic diet have shown decreased astroglial response in the vicinity of Aβ plaques and decreased expression of the pro-inflammatory cytokine interferon-γ in astrocytes. These findings correlate with transcriptional up-regulation of the ROS detoxifying mechanisms Sirt1 and Pparg, thus linking triheptanoin with improved mitochondrial status. Present findings support the concept that ketogenic diets supplemented with anaplerotic compounds can be considered potential therapeutic strategies at early stages of Alzheimer's disease.

Triheptanoin Protects Motor Neurons and Delays the Onset of Motor Symptoms in a Mouse Model of Amyotrophic Lateral Sclerosis

“…Based on the previous findings that triheptanoin diminished abnormalities in brain energy metabolism in different models and patients with CNS disorders [55,56,59,60] it is likely that improvements in ATP production contribute to triheptanoin’s neuroprotective effects. In addition, in an Alzheimer’s Disease model, triheptanoin in the context of a ketogenic diet increased the expression of the mRNA levels of Sirt1 , Pparg , Sod1 and Sod2 [75]. Sirtuin 1 and PPAR-γ are regulators of lipid and glucose metabolism as well as mitochondrial respiration and oxidative stress.…”

Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments

“…The ability of triheptanoin to provide both acetyl-CoA and propionyl-CoA makes it an ideal metabolic treatment for disorders with deficient levels of TCA cycle intermediates and impairments in energy production. For instance, triheptanoin alleviated metabolic disturbances associated with several neurological and neuromuscular disorders and improved symptoms in models of epilepsy (Willis et al, 2010; Thomas et al, 2012; Hadera et al, 2014), Canavan disease (Francis et al, 2014), autism disorders (Park et al, 2014) and Alzheimer's Disease (Aso et al, 2013) as well as patients and a mouse model of glucose transporter 1 deficiency (Marin-Valencia et al, 2013; Pascual et al, 2014; Mochel et al, 2016), and patients with Huntington's disease (Mochel et al, 2010; Adanyeguh et al, 2015). In chronically “epileptic” mice it was shown that triheptanoin partially restores reduced TCA cycle intermediate and metabolite levels (Willis et al, 2010; Hadera et al, 2014).…”

Comorbidities in Neurology: Is adenosine the common link?

“…KD therapy is remarkably effective in preventing seizures in epilepsy while providing additional benefits to cognitive function and overall well-being (Freeman, 2009; Kossoff and Rho, 2009; Lutas and Yellen, 2013; Masino and Rho, 2012). Currently KD therapy is considered for the treatment of Alzheimer’s disease (Aso et al, 2013; Van der Auwera et al, 2005), Parkinson’s disease (Cheng et al, 2009), and amyotrophic lateral sclerosis (Zhao et al, 2006). It may well be that a therapeutic intervention known to increase adenosine signaling in the brain has therapeutic promise for a wide range of neurological and neuropsychiatric disorders.…”