Microanalytical Peptide-Peptidase Profiling of the Brain Renin-Angiotensin System in a Genetically Diverse Alzheimer's Disease Mouse Model

Summary/Abstract High blood pressure is considered a risk factor for dementia and Alzheimer's disease (AD) progression. The renin-angiotensin system (RAS) is a hormonal and neuropeptide system that regulates blood pressure and is implicated in cardiovascular-neurodegenerative diseases, and as a potential target for dementia and AD treatment. While the function of the circulatory RAS in

diseases such as hypertension is well-known, its role in the brain particularly in brain areas affected by dementia and AD remains unclear. Using a genetically diverse humanized AD mouse model and new-generation ultrahigh-sensitivity mass spectrometry, this proposal will focus on elucidating the role of the brain RAS and hypertension risk in AD. We will focus our

efforts across three objectives: (1) Measure the profiles of brain angiotensin peptides and peptidases in genetically diverse AD-BXD mice and the impact of susceptibility and resilience to late-onset Alzheimer's disease (LOAD); (2) Determine the effects of hypertension on the angiotensin peptide–peptidase profiles in the early-onset (6 mo.) susceptible strains; (3) Utilize

bioinformatic tools for multivariate-statistical data analysis to uncover connections between the angiotensin peptide-peptidase system of the brain and the intricate interplay among cognitive, cardiovascular, behavioral, sex-dependent, and neuropathological factors, and whether these relationships contribute to the susceptibility and progression of dementia and the risk of

developing AD. These investigations hold the potential to unveil new biological mechanisms that contribute to dementia and AD risk and provide the opportunity for identifying new therapeutic directions that could potentially prevent or slow down the progression of dementia and AD.