The classical renin–angiotensin system (RAS), known as the angiotensin (Ang)-converting enzyme (ACE)/Ang II/Ang II type 1 (AT1) receptor axis, induces various organ damages including cognitive decline. On the other hand, the ACE2/Ang-(1–7)/Mas receptor axis has been highlighted as exerting antagonistic actions against the classical RAS axis in the cardiovascular system. However, the roles of the ACE2/Ang-(1–7)/Mas axis in cognitive function largely remain to be elucidated, and we therefore examined possible roles of ACE2 in cognitive function. Male, 10-week-old C57BL6 (wild type, WT) mice and ACE2 knockout (KO) mice were subjected to the Morris water maze task and Y maze test to evaluate cognitive function. ACE2KO mice exhibited significant impairment of cognitive function, compared with that in WT mice. Superoxide anion production increased in ACE2KO mice, with increased mRNA levels of NADPH oxidase subunit, p22^phox, p40^phox, p67^phox, and gp91^phox in the hippocampus of ACE2KO mice compared with WT mice. The protein level of SOD3 decreased in ACE2KO mice compared with WT mice. The AT1 receptor mRNA level in the hippocampus was higher in ACE2KO mice compared with WT mice. In contrast, the AT2 receptor mRNA level in the hippocampus did not differ between the two strains. Mas receptor mRNA was highly expressed in the hippocampus compared with the cortex. Brain-derived neurotrophic factor (BDNF) mRNA and protein levels were lower in the hippocampus in ACE2KO mice compared with WT mice. Taken together, ACE2 deficiency resulted in impaired cognitive function, probably at least in part because of enhanced oxidative stress and a decrease in BDNF.

经典的肾素-血管紧张素系统（RAS），称为血管紧张素（Ang）转换酶（ACE）/ Ang II / Ang II 1型（AT1）受体轴，会引起各种器官损害，包括认知能力下降。另一方面，ACE2 / Ang-（1-7）/ Mas受体轴已被强调对心血管系统中的经典RAS轴具有拮抗作用。然而，ACE2 / Ang-（1-7）/ Mas轴在认知功能中的作用仍有待阐明，因此，我们研究了ACE2在认知功能中的可能作用。对10周大的雄性C57BL6（野生型，WT）小鼠和ACE2基因敲除（KO）小鼠进行Morris水迷宫任务和Y迷宫测试，以评估其认知功能。与野生型小鼠相比，ACE2KO小鼠表现出明显的认知功能损害。^PHOX，P40 ^PHOX，P67 ^PHOX和亚基gp91 ^PHOX与WT小鼠相比ACE2KO小鼠海马。与野生型小鼠相比，ACE2KO小鼠的SOD3蛋白水平降低。与野生型小鼠相比，ACE2KO小鼠海马中的AT1受体mRNA水平更高。相比之下，两种菌株之间海马中的AT2受体mRNA水平没有差异。与皮质相比，Mas受体mRNA在海马中高表达。与野生型小鼠相比，ACE2KO小鼠海马中脑源性神经营养因子（BDNF）mRNA和蛋白水平较低。综上所述，ACE2缺乏症导致认知功能受损，这可能至少部分是由于氧化应激增强和BDNF降低所致。