Proteome profiling of brain vessels in a mouse model of cerebrovascular pathology

Abstract

A cerebrovascular pathology that involves altered protein levels or signaling of the transforming growth factor beta (TGF{beta}) family has been associated with various forms of dementia, including Alzheimer disease (AD) and vascular cognitive impairment and dementia (VCID). Transgenic mice overexpressing TGF{beta}1 in the brain (TGF mice) recap VCID-associated cerebrovascular pathology and develop cognitive deficits in old age or when submitted to comorbid cardiovascular risk-factors for dementia. Here, we characterized the cerebrovascular proteome of TGF mice using mass-spectrometry (MS) based quantitative proteomics. Cerebral arteries were surgically removed from 6-month-old-TGF and wild-type mice, proteins extracted and analyzed by gel-free nanoLC-MS/MS. We identified 3,602 proteins in brain vessels, with 20 demonstrating robust altered levels in TGF mice. For total and/or differentially-expressed proteins (p[≤]0.01, [≥]2-fold change), using multiple databases, we performed protein characterization, and identified proteins demonstrating RNA-transcripts in both mouse and human cerebrovascular cells, and known to be present in human-extracellular-vesicles (EVs). Dysregulated proteins point to perturbed brain vessel vasomotricity, remodeling, and inflammation. Given that blood-isolated EVs are novel, attractive and a minimally invasive biomarker discovery platform for the age-related dementias, several proteins identified in this study can potentially serve as VCID markers in humans.