Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, 855 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
Mol Neurobiol. 2020 Aug;57(8):3458-3484. doi: 10.1007/s12035-020-01964-9. Epub 2020 Jun 12.
Dementia is a potentially avertable tragedy, currently considered among the top 10 greatest global health challenges of the twenty-first century. Dementia not only robs individuals of their dignity and independence, it also has a ripple effect that starts with the inflicted individual's family and projects to the society as a whole. The constantly growing number of cases, along with the lack of effective treatments and socioeconomic impact, poses a serious threat to the sustainability of our health care system. Hence, there is a worldwide effort to identify new targets for the treatment of Alzheimer's disease (AD), the leading cause of dementia. Due to its multifactorial etiology and the recent clinical failure of several novel amyloid-β (Aβ) targeting therapies, a comprehensive "multitarget" approach may be most appropriate for managing this condition. Interestingly, renin angiotensin system (RAS) modulators were shown to positively impact all the factors involved in the pathophysiology of dementia including vascular dysfunction, Aβ accumulation, and associated cholinergic deficiency, in addition to tau hyperphosphorylation and insulin derangements. Furthermore, for many of these drugs, the preclinical evidence is also supported by epidemiological data and/or preliminary clinical trials. The purpose of this review is to provide a comprehensive update on the major causes of dementia including the risk factors, current diagnostic criteria, pathophysiology, and contemporary treatment strategies. Moreover, we highlight the angiotensin II receptor type 2 (AT2R) as an effective drug target and present ample evidence supporting its potential role and clinical applications in cognitive impairment to encourage further investigation in the clinical setting.
痴呆症是一种潜在可预防的悲剧，目前被认为是 21 世纪全球面临的 10 大最大健康挑战之一。痴呆症不仅剥夺了个人的尊严和独立性，而且还具有连锁反应，从受影响个人的家庭开始，并波及整个社会。病例数量不断增加，加上缺乏有效治疗和对社会经济的影响，对我们的医疗保健系统的可持续性构成了严重威胁。因此，全球都在努力寻找治疗阿尔茨海默病（AD）的新靶点，AD 是痴呆症的主要病因。由于其多因素病因和几种新型淀粉样蛋白-β（Aβ）靶向治疗的最近临床失败，全面的“多靶点”方法可能是管理这种疾病的最佳方法。有趣的是，肾素血管紧张素系统（RAS）调节剂已被证明对痴呆症病理生理学中涉及的所有因素（包括血管功能障碍、Aβ 积累和相关的胆碱能缺乏症）产生积极影响，此外还有tau 过度磷酸化和胰岛素紊乱。此外，对于许多这些药物，临床前证据也得到了流行病学数据和/或初步临床试验的支持。本综述的目的是全面更新痴呆症的主要病因，包括风险因素、当前的诊断标准、病理生理学和当代治疗策略。此外，我们强调血管紧张素 II 受体 2（AT2R）作为一种有效的药物靶点，并提供大量证据支持其在认知障碍中的潜在作用和临床应用，以鼓励在临床环境中进一步研究。
