Mechanisms of neuro- and cardioprotection of MAS agonists in the TAC model.

Abstract

Alzheimer's (AD) is a debilitating disease characterized by a loss of memory and executive function. A growing number of studies have shown a direct correlation between hypertension and increased risk of AD-like symptoms, including cognitive deficits, increased Aβ production and neuronal death. Furthermore, Renin-Angiotensin System (RAS) targeted anti-hypertensives reduce risk. This has prompted studies demonstrating that the protective arm of RAS, via activation of the MAS receptor, is reduced in AD patients, suggesting MAS agonists may protect against ROS production and exotoxicity while also increasing cognition and being cardioprotective. We hypothesize that MAS agonists can ameliorate AD-like pathology in mice using a model of heart failure - transverse aortic constriction (TAC). One week after TAC surgery, C57Bl/6J male mice (8-10wk) started treatment with saline or one of four Mas agonists. Four weeks after surgery, cardiac function was assessed by echocardiography followed by cognitive assessment (10 weeks) using novel object recognition. At 90days, brain, heart and blood were collected and analyzed for phenotypic and functional changes. TAC surgery induced marked morphological changes in cardiac tissue (cardiomyocyte area, fibrosis and apoptosis). The subsequent dysfunction manifested as decreases in standard cardiac measures of left ventricular function and by extension - cognition, which were rescued by MAS agonists. This treatment effect is partly due to a protection of the mitochondrial oxidative phosphorylation pathway rather than biogenesis. Specifically, marked ROS-induced mitochondrial dysfunction occurring within neurons and microglia were reduced with MAS agonist treatment. Further Seahorse analysis revealed a resistance to TAC-induced reductions in mitochondrial complex activity. This trend extended to the heart, improving outcomes for endothelial cells and cardiomyocytes. The Mas agonist RASRx1902 significantly decreased several measures of AD-like pathology in the TAC model with particular focus on cardioprotection and mitochondrial function, indicating that it may be beneficial in those with hypertension as a risk factor for AD development. Future work will focus on further characterizing RASRx1902 effects in affected cellular pathway changes, efficacy in a pilot study examining cerebral blood flow, blood brain barrier integrity, and effects on neuronal function.