The Role of Extracellular Matrix in Human Neurodegenerative Diseases

Abstract

The dense neuropil of the central nervous system leaves only limited space for extracellular substances free. The advent of immunohistochemistry, soon followed by advanced diagnostic tools, enabled us to explore the biochemical heterogeneity and compartmentalization of the brain extracellular matrix in exploratory and clinical research alike. The composition of the extracellular matrix is critical to shape neuronal function; changes in its assembly trigger or reflect brain/spinal cord malfunction. In this study, we focus on extracellular matrix changes in neurodegenerative disorders. We summarize its phenotypic appearance and biochemical characteristics, as well as the major enzymes which regulate and remodel matrix establishment in disease. The specifically built basement membrane of the central nervous system, perineuronal nets and perisynaptic axonal coats can protect neurons from toxic agents, and biochemical analysis revealed how the individual glycosaminoglycan and proteoglycan components interact with these molecules. Depending on the site, type and progress of the disease, select matrix components can either proactively trigger the formation of disease-specific harmful products, or reactively accumulate, likely to reduce tissue breakdown and neuronal loss. We review the diagnostic use and the increasing importance of medical screening of extracellular matrix components, especially enzymes, which informs us about disease status and, better yet, allows us to forecast illness.

HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

“…Neurons in the PNNs also synthesise cell surface HS-PGs through which instructive ECM cues to cells may be enacted upon. Such ECM cues have instructive directional roles over correct neuronal functional properties, disruptions in such interactions can contribute to the development of neurological disorders [ 353 ]. Proteomic analysis of schizophrenia and AD neural tissues has demonstrated the many proteins involved in such disruptions in normal synaptic activity [ 354 ].…”

“…PNNs, neuronal cell surface receptors and interactive molecules in the ECM have roles in the pathophysiology of a number of psychiatric disorders including schizophrenia, autism and mood disorders, AD, and epilepsy [ 359 , 360 , 370 , 371 ]. Such interactions can potentially affect neuronal pre- and postsynaptic terminals [ 353 , 354 , 358 ]. Glial and astrocyte activation in neurodegenerative conditions may also affect crosstalk with neuronal cell populations that may modulate synaptic functions and plasticity leading to synaptic dysfunction.…”

Extracellular Matrix Regulation in Physiology and in Brain Disease

“…There are many reports of ECM alterations, including degradation, overproduction, and altered composition, in brain conditions such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), schizophrenia, autism spectrum disorder (ASD), pain, and epilepsy [ 15 , 16 , 17 , 18 , 19 ]. The components of ECM that regulate its degradation are enzymes including matrix metalloproteinases (MMPs), disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTs), hyaluronidases/chondroitinases, and plasmin, and their regulators including tissue inhibitors of metalloproteinases (TIMPs), tissue plasminogen activator (tPA), and plasminogen activator inhibitor.…”

“…In this brief review, we aim to discuss alterations in the expression of ECM genes in various brain disease states, the role of the transcriptional regulators HIF-1 and AhR in ECM gene expression, and the role microglia play in PNN regulation. We refer to other reviews for other aspects of ECM regulation and function [ 3 , 5 , 8 , 10 , 12 , 13 , 15 , 16 , 18 , 27 , 28 , 29 , 30 ].…”

Editorial: Role of extracellular matrix in neurodevelopment and neurodegeneration

“…Recently, an interplay between neurodegeneration, extra cellular space and matrix is reported in Parkinson's disease rodent model shedding light upon a neglected compartment for the diffusion of aggregated α-synuclein seeds (Soria et al, 2020 ). As reviewed recently by Pinter and Alpar, selective ECM components can either proactively trigger the disease-specific toxicants, or reactively accumulate them in ECM (Pinter and Alpar, 2022 ). Several studies have linked ECM to neurodegeneration in Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS) and Huntington diseases but there are still huge knowledge gaps regarding the role of ECM and therapeutic potential of its components.…”