Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease

Alexandra Pokhilko, Gaia Brezzo, Lahiru Handunnetthi, Raphael Heilig, Rachel Lennon, Colin Smith, Stuart M Allan, Alessandra Granata, Sanjay Sinha, Tao Wang, Hugh S Markus, Alexandra Naba, Roman Fischer, Tom Van Agtmael, Karen Horsburgh, M Zameel Cader

Research output: Contribution to journalArticlepeer-review

Abstract

The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as COL4A1, COL4A2, VCAN and APOE were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease.
Original languageEnglish
Pages (from-to)2423–2438
JournalJournal of Cerebral Blood Flow and Metabolism
Volume41
Issue number9
Early online date17 Mar 2021
DOIs
Publication statusE-pub ahead of print - 17 Mar 2021

Keywords

  • Basement Membrane
  • matrisome
  • proteome
  • Cerebrovascular
  • Extracellular Matrix

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