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 Aβ42 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.

中文翻译：

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ACE2 激活可防止认知能力下降并减少阿尔茨海默病 Tg2576 小鼠模型中的淀粉样蛋白病理。

中年高血压和脑血管功能障碍与晚年痴呆风险增加有关，包括阿尔茨海默病 (AD)。经典的肾素-血管紧张素系统 (cRAS) 是血压的生理调节剂，在脑内独立发挥作用，在 AD 中过度活跃。在动物模型和人体病理学研究中，靶向 cRAS 的抗高血压药物与 AD 发病率降低、认知衰退延迟发生以及 Aβ 和 tau 水平降低有关。cRAS 活性由下游调节 RAS 通路 (rRAS) 调节，该通路在 AD 中不活跃，与人类 AD 的病理特征和 CNS 疾病动物模型的认知下降密切相关。我们现在表明，脑 ACE2 活性（rRAS 的主要效应物）的增强，通过腹膜内施用醋酸二胺 (DIZE)，一种既定的 ACE2 激活剂，降低了中年（13-14 个月大）有症状的 Tg2576 小鼠的海马 Aβ 并恢复了认知。我们证实 DIZE 的保护作用是通过 ACE2 直接介导的，并且与海马可溶性 Aβ42 和 IL1-β 水平降低有关。DIZE 恢复了海马 MasR 水平，同时增加了 Tg2576 小鼠海马突触体中 NMDA NR2B 和下游 ERK 信号传导的表达。对症状前的 9-10 个月大的 Tg2576 小鼠慢性（10 周）施用 DIZE，对认知受损的 12-13 个月大的小鼠进行急性（10 天）治疗，可防止认知障碍的发展。