Abstract WP266: Deficiency of Angiotensin Converting Enzyme 2 Causes Deterioration of Cognitive Function

Abstract

Introduction: 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 damage 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. Methods: Male 10-week-old C57BL6 (wild-type: WT) mice and ACE2 knockout (KO) mice were subjected to the Morris water maze task to evaluate spatial cognitive function. Vascular dementia model were induced by bilateral common carotid artery stenosis (BCAS). The Morris water maze task was performed 6 weeks after BCAS operation. Results: ACE2KO mice exhibited significant impairment of spatial cognitive function, compared with that in WT mice, without significant difference in cerebral blood flow determined by laser speckle flowmetry and morphological changes in the hippocampus between both strains. Superoxide anion production in the hippocampus tended to be increased in ACE2KO mice, with increased mRNA levels of NADPH oxidase subunit in the hippocampus of ACE2KO compared with WT mice. Protein level of superoxide dismutase (SOD) 3 tended to be decreased in ACE2KO mice compared with WT mice. AT1 receptor mRNA level in the hippocampus was higher in ACE2KO mice compared with WT mice. In contrast, 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, with no significant difference between ACE2KO and WT mice. Brain-derived neurotrophic factor (BDNF) mRNA was lower in the hippocampus in ACE2KO mice compared with WT mice. Escape latency after BCAS was prolonged in WT mice compared with sham operated mice, whereas impaired cognitive function in ACE2 KO mice was not further exaggerated after BCAS. Conclusion: Taken together ACE2 deficiency resulted in impaired cognitive function probably due to enhanced oxidative stress and a decrease in BDNF.