Deep quantitative proteomics analysis of the brain vasculature in Alzheimer’s disease and related tauopathies.

Abstract

AbstractBackgroundDysfunction of neurovascular unit represents a major pathological hallmark of Alzheimer’s disease (AD) and age‐related cognitive impairment. Diminished blood flow and blood‐brain barrier breakdown have been linked to the accumulation of amyloid‐b (Ab) peptide in brain parenchyma and cerebral blood vessels. Additionally, cerebrovascular dysfunction has been associated with tau pathology in primary tauopathies, including progressive supranuclear palsy (PSP) where amyloid deposition is not present. Despite the significance of brain vasculature in maintaining the proper neuronal function, the proteomic profiles of cerebrovasculature remain poorly characterized.MethodsHere, for the first time we implemented a tandem mass tag spectrometry (TMT‐MS) approach to thoroughly examine proteomic features of human cerebrovasculature from postmortem brain tissues from AD, PSP, and non‐demented control individuals (N = 20‐24 cases/diagnosis) from the University of Pennsylvania School of Medicine Brain Bank. The human cerebrovasculature was isolated from frontal cortex using density‐mediated separation to purify blood vessels from parenchymal components.ResultsThe quantification of over 9,800 proteins allowed us to generate deep TMT protein co‐expression network consisting of 93 communities of proteins displaying wide biological heterogeneity associated with diverse brain pathologies. Importantly, the comparison of vascular proteome with proteomic data obtained from bulk brain tissues from the same individuals gave us a unique opportunity to interrogate the relationship and preservation between different data sets. We also explored how candidate gene products that confer the risk for AD or PSP map to the discovered protein modules.ConclusionsIn summary, by taking advantage of our network‐driven approach we nominated pathways strongly correlated with AD‐like neuropathological traits and vascular biology that could provide the foundation for our understanding of the mechanisms governing AD‐linked breakdown of BBB, dysregulation of the cerebral blood flow, and pathological accumulation of protein aggregates in human vasculature.