A Dietary Ketone Ester Normalizes Abnormal Behavior in a Mouse Model of Alzheimer’s Disease

Abstract

Because of a decreased sensitivity toward insulin, a key regulator of pyruvate dehydrogenase (PDH), Alzheimer’s patients have lower brain glucose utilization with reductions in Tricarboxylic Acid (TCA) cycle metabolites such as citrate, a precursor to n-acetyl-aspartate. In the 3xTgAd mouse model of Alzheimer’s disease (AD), aging mice also demonstrate low brain glucose metabolism. Ketone metabolism can overcome PDH inhibition and restore TCA cycle metabolites, thereby enhancing amino acid biosynthesis. A ketone ester of d-β-hydroxybutyrate was incorporated into a diet (Ket) and fed to 3xTgAd mice. A control group was fed a calorically matched diet (Cho). At 15 months of age, the exploratory and avoidance-related behavior patterns of the mice were evaluated. At 16.5 months of age, the animals were euthanized, and their hippocampi were analyzed for citrate, α-ketoglutarate, and amino acids. In the hippocampi of the Ket-fed mice, there were higher concentrations of citrate and α-ketoglutarate as well as higher concentrations of glutamate, aspartate and n-acetyl-aspartate compared with controls. There were positive associations between (1) concentrations of aspartate and n-acetyl-aspartate (n = 14, R = 0.9327), and (2) α-ketoglutarate and glutamate (n = 14, R = 0.8521) in animals maintained on either diet. Hippocampal n-acetyl-aspartate predicted the outcome of several exploratory and avoidance-related behaviors. Ketosis restored citrate and α-ketoglutarate in the hippocampi of aging mice. Higher concentrations of n-acetyl-aspartate corresponded with greater exploratory activity and reduced avoidance-related behavior.

Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents

“…A recent study in a mouse model of Alzheimer’s disease (triple transgenic Alzheimer’s 3xTgAD, which shows reduced brain glucose utilization) demonstrated that BHB ketone ester intervention, compared to a regular chow diet, elevated hippocampal glutamate and α-glutarate (a precursor of glutamate), and glutamate and α-glutarate levels intercorrelated positively in both groups. This may indicate that metabolic ketosis furnishes mitochondria with TCA cycle substrates ( 17 ). Furthermore, a 4-month KD elevated Glu and glutamine in young adult rats ( 36 ), and although human patients with epilepsy did not show differences in posterior cingulate cortical Glu measures compared to controls, elevated Glu concentrations predicted short-term freedom from seizures, hence indicating clinical relevance of elevated Glu in epilepsy ( 37 ).…”

Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases

“…EKSs may exert these beneficial effects via increased ketone body level, which can improve mitochondrial functions. For example, increased level of βHB can compensate glucose hypometabolism-generated decrease in energy source in human and restore ATP synthesis [ 16 , 289 , 318 , 319 , 323 ]. In fact, glucose hypometabolism may contribute to the development of, for example, Alzheimer’s disease [ 324 , 325 ].…”

An Alternative Enzymatic Route to the Ergogenic Ketone Body Ester (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate

“…The reaction mixture was filtered to remove the enzyme and evaporated under reduced pressure (80 mm Hg) to separate unreacted ethyl ester (S)-2 as the distillate (0.4 g, 3.0 mmol), 40% yield (91% ee), from the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (R,R)-4 (0.64 g, 3.6 mmol),48% yiled (>90% dr). 1…”

“…The ketone bodies (R)-3-hydroxybutyrate and acetoacetate, are short chain acids produced by the liver from the free fatty acids released from adipose tissue. The blood ketone bodies concentration normally ranges below 1 mM [1] increasing up to 5−7 mM during prolonged fasts [2]. Under this metabolic condition, known as ketosis, ketone bodies efficiently replace glucose as respiratory substrate, furnishing a higher ATP yield with respect to pyruvate, the end-product of glycolysis [3].…”