Hertz Leif, Chen Ye, Waagepetersen Helle S
Laboratory of Metabolic Brain Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, China.
Henry M. Jackson Foundation, Bethesda, Maryland, USA.
J Neurochem. 2015 Jul;134(1):7-20. doi: 10.1111/jnc.13107. Epub 2015 Apr 23.
Diet supplementation with ketone bodies (acetoacetate and β-hydroxybuturate) or medium-length fatty acids generating ketone bodies has consistently been found to cause modest improvement of mental function in Alzheimer's patients. It was suggested that the therapeutic effect might be more pronounced if treatment was begun at a pre-clinical stage of the disease instead of well after its manifestation. The pre-clinical stage is characterized by decade-long glucose hypometabolism in brain, but ketone body metabolism is intact even initially after disease manifestation. One reason for the impaired glucose metabolism may be early destruction of the noradrenergic brain stem nucleus, locus coeruleus, which stimulates glucose metabolism, at least in astrocytes. These glial cells are essential in Alzheimer pathogenesis. The β-amyloid peptide Aβ interferes with their cholinergic innervation, which impairs synaptic function because of diminished astrocytic glutamate release. Aβ also reduces glucose metabolism and causes hyperexcitability. Ketone bodies are similarly used against seizures, but the effectively used concentrations are so high that they must interfere with glucose metabolism and de novo synthesis of neurotransmitter glutamate, reducing neuronal glutamatergic signaling. The lower ketone body concentrations used in Alzheimer's disease may owe their effect to support of energy metabolism, but might also inhibit release of gliotransmitter glutamate. Alzheimer's disease is a panglial-neuronal disorder with long-standing brain hypometabolism, aberrations in both neuronal and astrocytic glucose metabolism, inflammation, hyperexcitability, and dementia. Relatively low doses of β-hydroxybutyrate can have an ameliorating effect on cognitive function. This could be because of metabolic supplementation or inhibition of Aβ-induced release of glutamate as gliotransmitter, which is likely to reduce hyperexcitability and inflammation. The therapeutic β-hydroxybutyrate doses are too low to reduce neuronally released glutamate.
用酮体（乙酰乙酸和β-羟基丁酸）或能产生酮体的中链脂肪酸进行饮食补充，一直被发现能使阿尔茨海默病患者的心理功能有适度改善。有人提出，如果在疾病的临床前期而非症状明显出现后很久才开始治疗，治疗效果可能会更显著。临床前期的特征是大脑长达数十年的葡萄糖代谢减退，但即使在疾病症状出现后初期，酮体代谢仍保持完整。葡萄糖代谢受损的一个原因可能是去甲肾上腺素能脑干核蓝斑早期遭到破坏，而蓝斑至少在星形胶质细胞中能刺激葡萄糖代谢。这些神经胶质细胞在阿尔茨海默病发病机制中至关重要。β-淀粉样肽Aβ会干扰其胆碱能神经支配，由于星形胶质细胞谷氨酸释放减少，这会损害突触功能。Aβ还会降低葡萄糖代谢并导致兴奋性过高。酮体同样可用于对抗癫痫发作，但有效使用浓度过高，以至于它们必定会干扰葡萄糖代谢和神经递质谷氨酸的从头合成，从而减少神经元的谷氨酸能信号传递。在阿尔茨海默病中使用的较低酮体浓度可能因其对能量代谢的支持作用而产生效果，但也可能抑制神经胶质递质谷氨酸的释放。阿尔茨海默病是一种涉及神经胶质细胞和神经元的疾病，伴有长期的大脑代谢减退、神经元和星形胶质细胞葡萄糖代谢异常、炎症、兴奋性过高以及痴呆。相对低剂量的β-羟基丁酸对认知功能可能有改善作用。这可能是由于代谢补充或抑制了Aβ诱导的作为神经胶质递质的谷氨酸释放，这可能会降低兴奋性过高和炎症反应。治疗用的β-羟基丁酸剂量过低，无法减少神经元释放的谷氨酸。
