Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland; Institute of Pharmacology and Toxicology, Department of Medicine, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Pharmacol Res. 2020 Apr;154:104230. doi: 10.1016/j.phrs.2019.04.014. Epub 2019 Apr 13.
With ageing of the global society, the frequency of ageing-related neurodegenerative diseases such as Alzheimer`s disease (AD) is on the rise worldwide. Currently, there is no cure for AD, and the four drugs approved for AD only have very small effects on AD symptoms. Consequently, there are enormous efforts worldwide to identify new targets for treatment of AD. Approaches that interfere with classical neuropathologic features of AD, such as extracellular senile plaques formed of aggregated amyloid-beta (Abeta), and intracellular neurofibrillary tangles of hyperphosphorylated tau have not been successful so far. In search for a treatment approach of AD, we found that inhibition of the angiotensin-converting enzyme (ACE) by a centrally acting ACE inhibitor retards symptoms of neurodegeneration, Abeta plaque formation and tau hyperphosphorylation in experimental models of AD. Our approach is currently being investigated in a clinical setting. Initial evidence with AD patients shows that a brain-penetrating ACE inhibitor counteracts the process of neurodegeneration and dementia. Moreover, centrally acting ACE inhibitors given in addition to the standard therapy, cholinesterase inhibition, can improve cognitive function of AD patients for several months. This is one of the most promising results for AD treatment since more than a decade.
随着全球社会老龄化,与衰老相关的神经退行性疾病(如阿尔茨海默病(AD))的频率在全球范围内呈上升趋势。目前,尚无治愈 AD 的方法,而批准用于 AD 的四种药物仅对 AD 症状有很小的作用。因此,全世界都在努力寻找治疗 AD 的新靶点。迄今为止,干扰 AD 的经典神经病理学特征(如由聚集的淀粉样蛋白-β(Abeta)形成的细胞外老年斑和过度磷酸化的 tau 形成的细胞内神经原纤维缠结)的方法并不成功。在寻找 AD 的治疗方法时,我们发现血管紧张素转换酶(ACE)抑制剂通过中枢作用抑制 ACE 可延缓 AD 实验模型中的神经退行性变、Abeta 斑块形成和 tau 过度磷酸化的症状。我们的方法目前正在临床研究中。初步证据表明,穿透血脑屏障的 ACE 抑制剂可抵抗神经退行性变和痴呆的进程。此外,中枢作用 ACE 抑制剂与标准治疗(胆碱酯酶抑制)联合使用可以改善 AD 患者的认知功能长达数月。这是 AD 治疗 10 多年来最有希望的结果之一。