Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function

Abstract

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, p22phox, p40phox, p67phox, and gp91phox 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. Angiotensin-converting enzyme 2 (ACE2), an enzyme that regulates a cellular pathway linked to blood pressure regulation, is found to play an important role in maintaining normal cognitive functions. Masatsugu Horiuchi and his colleagues from the medical school of Ehime University in Japan, using classical behavioral tests, compared the cognitive functions of mice without ACE2 with those of normal mice, and found impaired spatial learning and memory in the former. Among the ACE2-deficient mice, the researchers observed an increased production of free radicals and a decrease of an important learning-related nerve growth factor, which might explain their impaired cognitive functions. The study helps elucidate cognitive effects of the protective arm of the hormone system that regulates blood pressure, with potential applications in the prevention of cognitive decline in diseases such as hypertension and diabetes.