School of Psychology, Cardiff University, Cardiff, CF10 3AT, UK.
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK.
Acta Neuropathol. 2020 Mar;139(3):485-502. doi: 10.1007/s00401-019-02098-6. Epub 2020 Jan 25.
Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9-10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12-13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.
中年高血压和脑血管功能障碍与晚年痴呆症（包括阿尔茨海默病[AD]）的风险增加有关。经典的肾素-血管紧张素系统（cRAS）是血压的生理调节剂，在大脑中独立发挥作用，在 AD 中过度活跃。针对 cRAS 的降压药物与 AD 发病率降低、认知能力下降延迟以及动物模型和人类病理研究中 Aβ和 tau 水平降低有关。cRAS 活性由下游调节 RAS 途径（rRAS）调节，AD 中 rRAS 活性降低，与人类 AD 的病理标志物以及中枢神经系统疾病动物模型中的认知衰退强烈相关。我们现在表明，通过腹腔内给予二甲氮嗪（DIZE）增强大脑 ACE2 活性，作为 rRAS 的主要效应物，可降低海马 Aβ并恢复中年（13-14 月龄）症状性 Tg2576 小鼠的认知能力。我们证实，DIZE 的保护作用是通过 ACE2 直接介导的，与海马可溶性 Aβ和 IL1-β水平降低有关。DIZE 恢复了 Tg2576 小鼠海马 MasR 水平，同时增加了海马突触体中 NMDA NR2B 和下游 ERK 信号表达。在无症状的 9-10 月龄 Tg2576 小鼠中进行慢性（10 周）DIZE 给药，以及在认知障碍的 12-13 月龄小鼠中进行急性（10 天）治疗，可预防认知障碍的发展。这些数据表明，ACE2 增强可预防和逆转 AD 临床前模型中海马淀粉样蛋白相关的病理和认知障碍。
