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

ABSTRACT: 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.

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ORGANISM(S): Rattus Norvegicus (rat) Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Joakim Bastrup

LAB HEAD: Thomas Jepps

PROVIDER: PXD057298 | Pride | 2026-02-13

REPOSITORIES: Pride

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Project description:Background: The vascular wall of small arteries is heavily affected by high blood pressure. However, the underlying mechanisms causing vascular changes are not fully elucidated. Using a novel data-independent acquisition mass spectrometry (DIA-MS) approach, we aimed to determine the proteomic changes in small mesenteric arteries during early-onset high blood pressure in a rat model of hypertension. Methods: Snap frozen small mesenteric and renal arteries from the spontaneous hypertension rat (SHR) model and Wistar Kyoto (WKY) control rats were collected from two time points (6- and 12-weels of age) and analyzed by a label free quantitative DIA-MS workflow. Mesenteric arteries from Wister Hannover rats were included as an additional control to clarify genetic drift caused by selective inbreeding. Results: We identified a total of 3956 consistent proteins in the mesenteric artery wall and found that 286 proteins were significantly regulated in 12-weeks old SHRs compared to WKY controls. Comparing to an in silico matrisome database, we identified 38 extracellular matrix-associated proteins that could distinguish SHRs from WKY controls. Furthermore, when comparing the significantly regulated proteins identified in mesenteric and renal arteries, we identified 18 proteins, including Serpina3l, Igg-2a, ENSRNOG00000049829, Acyp2, Enpp3, Lss, Acaa1a, Basp1, an isoform of Basp1, Flot1, Flot2, Gstt1, Nit1, Ppid, Ikbkap, Poglut3, P4ha2 and Usp15, that were changed in both vascular beds. These proteins were associated with vital cellular processes, such as dyslipidemia, protease inhibition, remodeling and generation of reactive oxygen species. Majority of the identified proteins and pathways were associated with hypertension, and mapping the underlying changes help understanding the pathological processes occurring in the arterial wall during early-onset hypertension. Conclusions: Our data provides an in-depth analysis of the proteomic architecture of the mesenteric and renal artery wall from SHRs and WKY control rats. We identified 18 novel candidate proteins that highlights critical changes in small arteries of the SHR.

			Action	DRS
	HumanADandCAA_MSRawFiles.zip	Other
	HumanControl_MSRawFiles.zip	Other
	MSrawfiles.xlsx	Xlsx
	Rats_MSRawFiles.zip	Other
	UP000002494_10116.fasta	Fasta

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

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