Wan Lili, Lu Jin, Huang Jinlu, Huo Yan, Jiang Shan, Guo Cheng
Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Front Aging Neurosci. 2020 Sep 11;12:532386. doi: 10.3389/fnagi.2020.532386. eCollection 2020.
Acetylcholinesterase inhibitors (AChEIs) including donepezil (DNP) are considered to be the most promising therapeutic possibilities of Alzheimer's disease (AD). The response to DNP in AD patients varies and it is valuable to identify the potential markers that can predict the efficacy. Moreover, DNP has been found to affect bone function, but the exact mechanism is still unclear. Lipids and adipokine may link to AD and DNP directly or indirectly and might be potential biomarkers or therapeutic drug targets. The goal of this study was to investigate the relationships among adiponectin (APN), lipids levels, and the response to DNP, and to identify whether the effect of DNP in AD treatment is related to its effect on the level of APN in systemic circulation. The study recruited 85 AD patients with DNP treatment, of whom 47 were DNP responders and 38 were DNP nonresponders. The Mini-Mental State Examination was performed to evaluate the memory impairment. Plasma APN was measured with ELISA. The genotypes of single nucleotide polymorphisms rs1501299 and rs22417661 in APN for each patient were identified. Plasma lipids were quantified with gas chromatography coupled with mass spectrometry. Correlations among APN, lipid metabolomics, and DNP responded were evaluated. APN was significantly decreased in DNP responders. Methyl stearate and glycerol-3-phosphate, used for characterizing adipogenic differentiation, were significantly decreased in DNP responders compared to DNP nonresponders. APN and small-molecule lipids can be used as potential biomarkers to evaluate the efficacy of DNP. The results of metabolomics indicated that there was no change in the metabolic pathway of fatty acid metabolism and glucose metabolism in DNP responders, suggesting that APN-related biological function did not decrease in DNP responders. Our result suggests that more attention should be pay to the sources and biological functions of APN in AD with DNP treatment.
包括多奈哌齐（DNP）在内的乙酰胆碱酯酶抑制剂（AChEIs）被认为是治疗阿尔茨海默病（AD）最具前景的方法。AD患者对DNP的反应各不相同，识别能够预测疗效的潜在标志物很有价值。此外，已发现DNP会影响骨功能，但其确切机制仍不清楚。脂质和脂肪因子可能直接或间接与AD和DNP相关，可能是潜在的生物标志物或治疗药物靶点。本研究的目的是调查脂联素（APN）、血脂水平与对DNP反应之间的关系，并确定DNP在AD治疗中的作用是否与其对全身循环中APN水平的影响有关。该研究招募了85名接受DNP治疗的AD患者，其中47名是DNP反应者，38名是DNP无反应者。进行简易精神状态检查以评估记忆障碍。用酶联免疫吸附测定法测量血浆APN。确定了每位患者APN中单核苷酸多态性rs1501299和rs22417661的基因型。用气相色谱-质谱联用法定量血浆脂质。评估了APN、脂质代谢组学和DNP反应之间的相关性。DNP反应者的APN显著降低。与DNP无反应者相比，用于表征脂肪生成分化的硬脂酸甲酯和3-磷酸甘油在DNP反应者中显著降低。APN和小分子脂质可作为评估DNP疗效的潜在生物标志物。代谢组学结果表明，DNP反应者的脂肪酸代谢和葡萄糖代谢途径没有变化，这表明DNP反应者中与APN相关的生物学功能没有降低。我们的结果表明，在接受DNP治疗的AD患者中，应更多地关注APN的来源和生物学功能。
