Medium chain triglycerides are easily converted to ketone bo

Medium chain triglycerides are easily converted to ketone bodies. A study assessing the effects of ketosis induced by the administration of medium chain triglycerides was performed in aged dogs, a natural model of amyloidosis [59]. The dogs received a 2g/kg/day dose of medium chain triglycerides for 2 months. Compared to age-matched controls, markedly improved mitochondrial function was observed in aged dogs receiving medium chain triglycerides [59]. This effect was most prominent in the parietal lobe. In addition, there was a trend towards a decrease in Aβ levels in the parietal lobe [59]. These results suggest that short-term administration of medium chain triglycerides improves energy metabolism in the aged canine brain. Mitochondrial bioenergetic deficits have been shown to be closely related to the pathogenesis of AD [60]. These deficits activate a cascade of neurotoxic outcomes, including an increase in oxidative stress and the production of Aβ, which impair synaptic functions and lead to neuronal death [61]. A decline in mitochondrial bioenergetics has also been demonstrated to precede AD pathology in the female triple-transgenic AD (3xTgAD) mouse model [62]. In the brains of these mice, a temporary increase in the expression of ketogenic markers was also found, indicating a compensatory energy production mechanism [62]. In order to investigate if this alternative energy supply could be preserved, the effects of 2-deoxy-D-glucose (2-DG) administration on axl inhibitor AD pathology were assessed [63]. 2-DG is known to competitively block glucose metabolism and to induce ketogenesis in the liver, i.e. a compensatory production of ketone bodies as alternative energy substrates. Six-month-old female 3xTgAD mice were fed either a diet containing 0.04% 2-DG or a regular diet (AIN-93G) for seven weeks. The 2-DG diet markedly increased serum ketone body levels and brain expression of enzymes required for ketone body metabolism. Mice fed the 2-DG diet showed a significant reduction of both amyloid precursor protein (APP) and amyloid beta (Aβ) oligomers as well as a significant increase in α-secretase and decrease in γ-secretase expression, indicating that 2-DG induced a shift towards a non-amyloidogenic pathway [63]. In comparison to the control diet, the 7-week dietary 2-DG administration significantly induced ketogenesis, sustained mitochondrial bioenergetic function, and reduced Aβ pathology. In summary, these preclinical findings suggest that the dietary 2-DG intervention can delay the progression of bioenergetic deficits and Aβ production in the brain [63]. The hypothesis that a ketone ester-based diet can ameliorate AD pathogenesis was tested in the 3xTgAD mouse model [64]. Beginning at a presymptomatic age, male 3xTgAD mice were fed either a diet containing a physiological enantiomeric precursor of ketone bodies or an isocaloric carbohydrate diet. The mice fed a precursor of ketone bodies showed reduced Aβ and hyperphosphorylated tau deposition in the hippocampus, amygdala and cortex [64]. In behavioral tests performed at 4 and 7 months following the initiation of the experimental diet, 3xTgAD mice exhibited significant improvements in learning and memory tests as assessed using the Morris water maze [64]. These results demonstrate that long-term feeding of ketone esters reduces Aβ accumulation and hyperphosphorylated tau pathology and improves cognitive functions in a mouse model of AD. The preclinical findings suggest that a ketone ester-containing diet can potentially retard the disease process and improve cognitive functions of patients with AD. Ketone bodies cannot provide additional citric acid cycle intermediates which limits the anabolic capacity of the cell. The supplementation of ketogenic diet with anaplerotic compounds such as triheptanoin may increase the effects of the diet [65]. The hypothesis that supplementation with triheptanoin can increase the beneficial effects of ketogenic diet was tested in a rodent model of familial AD, the APP/PS1 transgenic mouse. Three-month-old APP/PS1 mice were fed a ketogenic diet plus triheptanoin supplementation for three months. This treatment reduced the memory impairment of the mice at the age of 6 months. Aβ production and deposition were not significantly changed by either ketogenic diet alone or the combination diet [65]. However, mice fed with triheptanoin-rich ketogenic diet demonstrated a reduction in astroglial response in the vicinity of Aβ plaques and a decrease in the expression of the pro-inflammatory cytokine interferon-γ in astrocytes. Ketogenic diets supplemented with anaplerotic compounds may therefore delay cognitive impairment by acting via astrocytes in energy metabolism responses [65]. These results suggest the potential therapeutic utility of triheptanoin-rich ketogenic diets at early stages of AD.