Laboratory of Metabolic Control, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892, USA.
Int J Mol Sci. 2020 Feb 4;21(3):1044. doi: 10.3390/ijms21031044.
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.
由于对丙酮酸脱氢酶 (PDH) 的关键调节剂胰岛素的敏感性降低，阿尔茨海默病患者的大脑葡萄糖利用率降低，三羧酸 (TCA) 循环代谢物减少，如柠檬酸，它是前体 n-乙酰天冬氨酸。在阿尔茨海默病 (AD) 的 3xTgAd 小鼠模型中，衰老的小鼠也表现出低脑葡萄糖代谢。酮代谢可以克服 PDH 抑制并恢复 TCA 循环代谢物，从而增强氨基酸合成。β-羟基丁酸的酮酯被纳入饮食 (Ket) 并喂给 3xTgAd 小鼠。对照组喂以热量匹配的饮食 (Cho)。在 15 个月大时，评估了小鼠的探索和回避相关行为模式。在 16.5 个月大时，处死动物并分析其海马中的柠檬酸、α-酮戊二酸和氨基酸。在 Ket 喂养的小鼠的海马中，柠檬酸和α-酮戊二酸的浓度更高，谷氨酸、天冬氨酸和 n-乙酰天冬氨酸的浓度也更高，与对照组相比。在两种饮食喂养的动物中，（1）天冬氨酸和 n-乙酰天冬氨酸的浓度之间存在正相关（n = 14，R = 0.9327），（2）α-酮戊二酸和谷氨酸的浓度之间存在正相关（n = 14，R = 0.8521）。维持在两种饮食中的动物。海马体中的 n-乙酰天冬氨酸预测了几种探索和回避相关行为的结果。酮症恢复了衰老小鼠海马体中的柠檬酸和α-酮戊二酸。较高浓度的 n-乙酰天冬氨酸与更高的探索活动和减少的回避相关行为相对应。
