Departments of Psychology, Veterinary and Comparative, Anatomy, Pharmacology and Physiology, and Programs in Neuroscience and Biotechnology, Washington State University, Pullman, Pullman, WA 99164-4820, USA.
Exp Neurol. 2010 Jun;223(2):326-33. doi: 10.1016/j.expneurol.2009.09.012. Epub 2009 Sep 24.
Alzheimer's disease (AD) has become a major world-wide health problem with ever rising costs associated with the treatment and care of afflicted individuals. As life expectancy has increased the occurrence of dementia has also increased. Hypertension during middle adulthood is correlated with a significantly elevated risk of cognitive impairment later in life. Treatment with antihypertensive drugs, particularly angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), has been reported to reduce the likelihood and slow the progression of AD; however, the use of ACE inhibitors may be accompanied by an increase in amyloid beta protein(1-42) accumulation. This review summarizes available information regarding the brain renin-angiotensin system (RAS), and specifically the efficacy of ACE inhibitors as anti-dementia agents, and considers the recently discovered AT(4) receptor and associated agonist drugs as potential new therapeutic targets to treat memory impairments associated with AD. We conclude with a description of recent efforts by members of our laboratory to develop blood-brain barrier penetrant angiotensin IV analogue drugs that facilitate cognition in animal models of AD. These efforts have resulted in a small molecule with desirable hydrophobicity characteristics that shows promise with respect to memory facilitation when peripherally administered.
阿尔茨海默病（AD）已成为一个全球性的重大健康问题，与治疗和护理患者相关的成本不断上升。随着预期寿命的延长，痴呆的发病率也有所增加。中年时期的高血压与晚年认知障碍的风险显著升高有关。抗高血压药物的治疗，特别是血管紧张素转换酶（ACE）抑制剂和血管紧张素受体阻滞剂（ARBs），已被报道可降低 AD 的可能性并减缓其进展；然而，ACE 抑制剂的使用可能伴随着淀粉样β蛋白（1-42）积累的增加。这篇综述总结了有关大脑肾素-血管紧张素系统（RAS）的现有信息，特别是 ACE 抑制剂作为抗痴呆药物的疗效，并考虑了最近发现的 AT（4）受体及其相关激动剂药物作为治疗与 AD 相关记忆障碍的潜在新治疗靶点。我们最后描述了我们实验室成员最近为开发穿透血脑屏障的血管紧张素 IV 类似物药物所做的努力，这些药物可改善 AD 动物模型的认知能力。这些努力产生了一种具有理想疏水性特征的小分子，当外周给药时，在记忆促进方面显示出前景。
