Cellular and Molecular Life Sciences

, Volume 76, Issue 16, pp 3229–3248 | Cite as

Demystifying the extracellular matrix and its proteolytic remodeling in the brain: structural and functional insights

  • Venkat Raghavan Krishnaswamy
  • Amit Benbenishty
  • Pablo Blinder
  • Irit SagiEmail author


The extracellular matrix (ECM) plays diverse roles in several physiological and pathological conditions. In the brain, the ECM is unique both in its composition and in functions. Furthermore, almost all the cells in the central nervous system contribute to different aspects of this intricate structure. Brain ECM, enriched with proteoglycans and other small proteins, aggregate into distinct structures around neurons and oligodendrocytes. These special structures have cardinal functions in the normal functioning of the brain, such as learning, memory, and synapse regulation. In this review, we have compiled the current knowledge about the structure and function of important ECM molecules in the brain and their proteolytic remodeling by matrix metalloproteinases and other enzymes, highlighting the special structures they form. In particular, the proteoglycans in brain ECM, which are essential for several vital functions, are emphasized in detail.


Brain Extracellular matrix Matrix remodeling Nodes of Ranvier Perineuronal nets Proteases Synapses 



α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor


Activator protein 1


Autism spectrum disorders


Brain-specific hyaluronan-binding protein


Cell adhesion molecule




Central nervous system


cAMP-response element-binding


Complement regulatory protein


Chondroitin sulfate proteoglycan


Deleted in colorectal cancer


Extracellular domain


Extracellular matrix




Hyaluronic acid


Hyaluronan and proteoglycan link protein 1


Hyaluronan synthase


Heparin sulfate proteoglycan


Long-term depression


Long-term potentiation


l-type voltage-dependent Ca2+ channels


Matrix metalloproteinase


N-methyl-d-aspartate receptor


Neuronal activity-regulated pentraxin




Neuroglycan C


Neuron–glia-related cell adhesion molecule


Perineuronal net


Phosphacan short isoform


Proteoglycan tandem repeat


Receptor-type protein-tyrosine phosphatase


Sulfoglucuronyl glycolipid


Synaptosomal nerve-associated protein 25


Tissue inhibitor of MMPs






Tissue plasminogen activator



Irit Sagi is an Incumbent of the Maurizio Pontecorvo Professorial Chair and has received funding from the Israeli Science Foundation (1226/13), the European Research Council AdG (THZCALORIMETRY—DLV-695437), and the USA-Israel Binational Science Foundation (712506-01). She is grateful for the Azrieli Foundation for its generous grant to conduct research on the extracellular matrix of the brain.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Venkat Raghavan Krishnaswamy
    • 1
  • Amit Benbenishty
    • 1
  • Pablo Blinder
    • 2
    • 3
  • Irit Sagi
    • 1
    Email author
  1. 1.Department of Biological RegulationWeizmann Institute of ScienceRehovotIsrael
  2. 2.Neurobiology, Biochemistry and Biophysics SchoolTel Aviv UniversityTel AvivIsrael
  3. 3.Sagol School for NeuroscienceTel Aviv UniversityTel AvivIsrael

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