Shared proteomic signature between a rat model of hypertension and Alzheimer’s disease point to cerebrovascular changes in extracellular vesicles

Untreated hypertension is a risk factor for late-onset Alzheimer’s disease (AD). However, this association is not well understood, mainly due to the lack of animal models. The aim of this study was to reveal novel proteins and pathways that underlie AD associated with hypertension. Using untargeted proteomics, we analyzed brain samples from the frontal cortex of human AD (Braak stages 4-6), cerebral amyloid angiopathy (CAA), non-demented controls (Braak stages 0-3), aged (30 and 40 week-old) hypertensive rats, and age-matched normotensive Wistar Kyoto (WKY) controls. We identified 199 differentially expressed proteins (DEPs) when comparing 40-week-old SHRs to age-matched WKY control rats. Moreover, our analysis of human samples identify more than 1300 DEPs in AD when compared to control. Using a cross-species comparison, we identify 24 candidate proteins in the SHR model, whose trajectory pattern over hypertension progression align with those observed in the AD Braak staging progression. The identified candidate proteins associate significantly with the “Extracellular exosomes” pathway and are dysregulated around the cerebrovasculature in both SHR and AD brains. Our findings demonstrate cross-species translatability between AD and the SHR, and provide novel mechanistic insights into a shared dysregulation of extracellular vesicles.