Extracellular exosome signature links hypertension and Alzheimer’s disease

Untreated hypertension is a risk factor for late-onset Alzheimer's disease (AD); however, this association is not well understood. The aim of this study was to reveal protein signatures that bridge the pathophysiological changes in hypertension to AD. Using untargeted proteomics, we analyzed brain samples from aged (30- and 40-week-old) spontaneously hypertensive rats (SHRs, n = 12), and age-matched normotensive Wistar Kyoto (WKY, n = 8) controls, and human AD patients (Braak stages 4-6) (n = 30), cerebral amyloid angiopathy (CAA) (n = 5), non-demented controls (Braak stages 0-3) (n = 37). Differential expression and pathway analyses in SHRs highlighted the 'extracellular exosome' pathway. This pathway also showed significant associations to differentially expressed proteins in AD and CAA patients. Comparison between species identified 24 proteins in SHRs and AD, whose trajectory pattern over the progression of hypertension, aligned with those observed during AD Braak stage progression, compared to respective controls. The proteins were similarly associated with extracellular exosomes. Immunostaining and spatial proteomics support vesicle accumulation and dysregulated exosome protein signatures in the cerebrovasculature of both SHR and AD brains. Additionally, the extracellular exosome pathway-association was not identified in a traditional model of familial AD (5xFAD). Our findings demonstrate cross-species translatability between AD and the SHR and provide novel mechanistic insights into a shared dysregulation of cerebral artery-associated exosomes.