Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, China.
Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Curr Alzheimer Res. 2018;15(10):917-927. doi: 10.2174/1567205015666180601091818.
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by a multi-factorial etiology that is not completely understood. Donepezil is a first-line acetylcholinesterase inhibitor used for the treatment of AD that has been found, in addition to its potent acetylcholinesterase inhibitory effect, to act through other non-cholinergic mechanisms such as affecting mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator (PGC1α). Mitochondrial biogenesis and PGC-1α, at least in part, are associated with hepatic fatty acid oxidation and ketogenesis. Whether donepezil regulates ketogenesis in AD treatment remains unclear. Ketogenesis is important in the progression of AD and is a critical consideration during the therapeutic strategy selection for AD. Thus, our goals were to determine the differences in ketone bodies in patients with AD who were taking donepezil treatment and those who were not, to elucidate the potential effect of AD and donepezil therapy on ketone body metabolic parameters, and to discover the effect of donepezil therapy on ketogenesis in patients with AD.
Cross-sectional analysis was performed on plasma collected from 145 individuals, namely, elderly adults as healthy controls (n=30), newly diagnosed patients with AD (n=30), patients with AD who responded to donepezil therapy (n=48) and patients with AD who did not respond to donepezil therapy (n=37). Gas chromatography-mass spectrometry was performed to quantify the lipids in the plasma. The level of β-hydroxybutyrate, a metabolite, was determined by liquid chromatographytandem mass spectrometry, and to gain further insight into the effect of donepezil on ketogenesis, the effects of donepezil were investigated in a mouse model.
The level of β-hydroxybutyrate decreased in AD patients, and donepezil elevated the plasma level of β-hydroxybutyrate. Donepezil increased the plasma and liver levels of β-hydroxybutyrate in mice as well as the hepatic expression of PGC-1α and the mitochondrial expression of HMG-CoA synthetase 2 (HMGCS2) in response to fasting, causing a subsequent increase in ketogenesis.
Our study revealed that impaired ketogenesis is a metabolic feature of AD. Donepezil had effects on ketogenesis in mice and reversed the decrease in the level of β-hydroxybutyrate found in patients with AD.
阿尔茨海默病（AD）是一种复杂的神经退行性疾病，其病因具有多因素性，但尚未完全阐明。多奈哌齐是一种一线乙酰胆碱酯酶抑制剂，用于治疗 AD，除了具有强大的乙酰胆碱酯酶抑制作用外，还通过其他非胆碱能机制发挥作用，例如通过过氧化物酶体增殖物激活受体γ共激活因子（PGC1α）影响线粒体生物发生。线粒体生物发生和 PGC-1α 至少部分与肝脂肪酸氧化和酮体生成有关。多奈哌齐是否调节 AD 治疗中的酮体生成尚不清楚。酮体生成在 AD 的进展中很重要，并且是 AD 治疗策略选择的关键考虑因素。因此，我们的目标是确定接受多奈哌齐治疗的 AD 患者与未接受多奈哌齐治疗的 AD 患者之间酮体的差异，阐明 AD 和多奈哌齐治疗对酮体代谢参数的潜在影响，并发现多奈哌齐治疗对 AD 患者酮体生成的影响。
对来自 145 人的血浆进行了横断面分析，即健康对照组的老年人（n=30）、新诊断的 AD 患者（n=30）、对多奈哌齐治疗有反应的 AD 患者（n=48）和对多奈哌齐治疗无反应的 AD 患者（n=37）。采用气相色谱-质谱法测定血浆中的脂质。通过液相色谱-串联质谱法测定代谢物β-羟丁酸的水平，并进一步研究多奈哌齐对酮体生成的影响，在小鼠模型中研究了多奈哌齐的作用。
AD 患者的β-羟丁酸水平降低，多奈哌齐升高了血浆β-羟丁酸水平。多奈哌齐增加了小鼠的血浆和肝脏β-羟丁酸水平以及肝 PGC-1α 和 HMG-CoA 合成酶 2（HMGCS2）的线粒体表达，从而导致随后酮体生成增加。
我们的研究表明，酮体生成受损是 AD 的代谢特征。多奈哌齐对小鼠的酮体生成有影响，并逆转了 AD 患者β-羟丁酸水平的降低。
