MAS Agonist-Induced Mechanisms of Neuroprotection Using a Novel Vascular Dementia Model

Abstract

A 2020 report by the CDC showed that for 2018, roughly 8.2% of the total US population was diagnosed with diabetes, a high-risk factor for AD development. Further, there is a long-standing correlation showing that hypertension is twice as frequent among diabetics as among nondiabetics (Pell, 1967). In Chapter 2, data gleaned from the “Mariner” claims dataset using PearlDiver (a paid online medical data repository) was used to examine the protective effect of several antihypertensive drugs actually used in hypertensive treatment plans. Data showed that renin angiotensin system (RAS) modifying anti-hypertensive drugs significantly reduce the likelihood of a myriad of neurodegenerative outcomes when compared to non-RAS modifying anti-hypertensives.In effort to secure the translational potential of these insights, these studies involved analyzing the effects of a novel Mas agonist developed as a therapeutic for neuroprotection (and that proved cardioprotective) in the transverse aortic coarctation (TAC) model:- that has been shown to produce some hallmarks of Alzheimer’s pathology, including amyloid-beta accumulation, inflammation and cognitive impairment. In Chapters 3-5, TAC surgery induced marked cognitive decline, rescued by MAS agonist, which also prevented an increase in antigen presenting microglia, thought to be the primary driver of AD pathology. This treatment effect was determined to be due to mitophagy of dysfunctional mitochondrial units and biogenesis, and thus a reduction in mitochondrial dysfunction; in TAC mice, occurring more significantly in microglia and neurons. Mechanistic understanding involved bulk RNAseq analysis of RNA isolated from the hippocampus of mice undergoing TAC surgery as well as single nuclei RNAseq on samples isolated from the hippocampus and cortex of 5xFAD mice. A deep dive of RNAseq data from these studies revealed TAC surgery may induce reductions in gene expression for a number of neurotrophic factors, survival pathways and regulatory molecules that have been implicated in AD pathogenesis, APP processing, tauopathy, endothelial cell survival and compensatory mechanisms, as well as neuronal health and function. Genetic analysis, flow cytometry enhanced imaging and an MSD analysis of hippocampus for inflammatory markers showed that in all cases, the hypothesized increases in anti-inflammatory and decrease in pro-inflammatory cytokines, as well as changes decreases in mitochondrial dysfunction, and thus oxidative phosphorylation, BBB integrity and metabolism were addressed with treatment. These changes were exacerbated when age and APOE4 alleles are added as high-risk factors to the TAC model. In Chapter 6, this protective trend was extended to the heart, as TAC surgery induced marked morphological changes in cardiac tissue (cardiomyocyte area, fibrosis and apoptosis), MAS treatment improved outcomes for endothelial cells and cardiomyocytes. The subsequent dysfunction manifested as decreases in standard cardiac measures of left ventricular function were also ablated. In conclusion, the Mas agonist RASRx1902 was able to significantly decrease several measures of AD-like pathology in the TAC model, indicating that it might be effective in decreasing disease state in those with hypertension as risk factor for AD development. Future work should be focused on further characterizing treatment effects of RASRx1902 in biochemical measures of mitochondrial function, cellular pathway changes and evaluating efficacy of a concurrent pilot study examining cerebral blood flow and blood brain barrier integrity in TAC.