Experimental Neurology, Saarland University, Homburg, Saar, Germany.
Department of Psychiatry and Psychotherapy, University Medical Center Johannes Gutenberg-University, Mainz, Germany.
Sci Rep. 2021 Jul 27;11(1):15301. doi: 10.1038/s41598-021-94706-3.
Alzheimer's disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.
阿尔茨海默病（AD）是一种非常常见的神经退行性疾病，其特征是淀粉样β（Aβ）的积累。阿维 A，一种维 A 衍生物，已被批准用于治疗寻常型银屑病，可增加非淀粉样前体蛋白（APP）的处理，防止 Aβ的产生，并在 AD 小鼠模型中引起认知改善。作为一种意外的副作用，阿维 A 可能导致高血脂。在这里，我们分析了阿维 A 对 5xFAD 小鼠模型中脑组织和肝组织脂质组的影响。与文献一致，肝脏中的甘油三酯增加，伴随着 PCaa、鞘磷脂和酰基肉碱的增加，而 SM 种类减少。在大脑中，这些影响部分增强或相似，但也出现了反转。虽然 SM 和鞘磷脂有相似的影响，但 PCaa、TAG 和酰基肉碱在两种组织中表现出相反的影响。我们的研究结果强调，用于治疗 AD 的潜在药物应该谨慎监测脂质平衡，因为 APP 的处理本身会调节脂质代谢，药物可能会导致进一步的、意想不到的变化。此外，从其他组织获得的脑脂质平衡结果推断出效果应该谨慎考虑。就阿维 A 而言，脑鞘磷脂的增加可能在 AD 治疗中显示出更高的正概率，而其他结果，如 SM 的减少，则表明需要对接受治疗的患者进行医疗监测。
