Extracellular Matrix Regulation in Physiology and in Brain Disease

Abstract

The extracellular matrix (ECM) surrounds cells in the brain, providing structural and functional support. Emerging studies demonstrate that the ECM plays important roles during development, in the healthy adult brain, and in brain diseases. The aim of this review is to briefly discuss the physiological roles of the ECM and its contribution to the pathogenesis of brain disease, highlighting the gene expression changes, transcriptional factors involved, and a role for microglia in ECM regulation. Much of the research conducted thus far on disease states has focused on “omic” approaches that reveal differences in gene expression related to the ECM. Here, we review recent findings on alterations in the expression of ECM-associated genes in seizure, neuropathic pain, cerebellar ataxia, and age-related neurodegenerative disorders. Next, we discuss evidence implicating the transcription factor hypoxia-inducible factor 1 (HIF-1) in regulating the expression of ECM genes. HIF-1 is induced in response to hypoxia, and also targets genes involved in ECM remodeling, suggesting that hypoxia could contribute to ECM remodeling in disease conditions. We conclude by discussing the role microglia play in the regulation of the perineuronal nets (PNNs), a specialized form of ECM in the central nervous system. We show evidence that microglia can modulate PNNs in healthy and diseased brain states. Altogether, these findings suggest that ECM regulation is altered in brain disease, and highlight the role of HIF-1 and microglia in ECM remodeling.

Microglia promote extracellular matrix deposition and restrict excitatory synapse numbers in the mesolimbic dopamine system during healthy aging

“…The ECM can regulate synapse function through direct ECM-synapse interactions, control of extracellular ion concentrations, and by regulating access of phagocytic cells to synaptic elements (Soles et al, 2023; Soria et al, 2020; Tewari et al, 2022). Here we show that age-associated increases in VTA hyaluronan abundance ( Figure 1 ) arise alongside no change in Homer2 densities or deposition of hyaluronan at excitatory synapses ( Figure 6B, 6C ).…”

Systematic review and meta-analysis of dysregulated microRNAs derived from liquid biopsies as biomarkers for amyotrophic lateral sclerosis

“…This pathway encompasses target genes involved in fibronectin, collagen, and laminin (data not shown). The dysregulation of ECM gene expression is common to neurodegenerative diseases as it provides structural and functional support and plays a role in the proliferation and differentiation of neuronal progenitors, as well as in axonal growth and guidance [ 87 ]. Another highly significant pathway was the adherens junction, associated with hsa-miR-183–5p, hsa-miR-151a-5p, and hsa-miR-29b-3p.…”

Injectable Hydrogels for Nervous Tissue Repair—A Brief Review

“…The type of cells and their extracellular matrix are the key components that determine their functions and properties, such as cell proliferation, migration, and differentiation [ 47 ]. The extracellular matrix of the central nervous system is composed of an extracellular matrix formed by fibrous proteins such as elastin or collagen embedded in an amorphous gel formed by non-fibrous components, usually glycoproteins formed by a core protein, which include a highly organized scaffold that is connected to the surface of the cells by adhesive molecules [ 48 , 49 ].…”