Fibrotic Scar in Neurodegenerative Diseases

Abstract

The process of uncontrolled internal scarring, called fibrosis, is now emerging as a pathological feature shared by both peripheral and central nervous system diseases. In the CNS, damaged neurons are not replaced by tissue regeneration, and scar-forming cells such as endothelial cells, inflammatory immune cells, stromal fibroblasts, and astrocytes can persist chronically in brain and spinal cord lesions. Although this process was extensively described in acute CNS damages, novel evidence indicates the involvement of a fibrotic reaction in chronic CNS injuries as those occurring during neurodegenerative diseases, where inflammation and fibrosis fuel degeneration. In this mini review, we discuss recent advances around the role of fibrotic scar formation and function in different neurodegenerative conditions, particularly focusing on the rising role of scarring in the pathogenesis of amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease and highlighting the therapeutic relevance of targeting fibrotic scarring to slow and reverse neurodegeneration.

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

“…In the injured CNS, when damaged neurons do not induce neural tissue regeneration, scar-forming endothelial cells, inflammatory immune cells, stromal fibroblasts and astrocytes lay down a fibrotic scar in brain and spinal cord lesions. This scar stabilises damaged tissue areas, but it also restricts neural regeneration and functional recovery [ 142 , 143 , 144 ].…”

Niclosamide Targets Inflammatory and Profibrotic Pathways in Amyotrophic Lateral Sclerosis

“…Moreover, broblasts represent a cell type that can become resident in the nervous system during in ammation [38], as well as in skeletal muscle. Indeed, activated broblasts (deriving from endothelial cells, pericytes, immune cells) can be accounted as cellular players in the development of brosis and in ammation during several neurodegenerative conditions, including ALS [4,8,36,58]. Thus, the identi cation of the molecules and pathways involved in the transition of broblasts from a quiescent to an activated phenotype, when their homeostasis is disturbed, might unveil pathogenic mechanisms that occur in nervous and peripheral tissues and that can contribute to the disease progression.…”

“…Central and peripheral nerve pathology with in ammation and brosis is a major harmful mechanism contributing to degeneration [21,61]. In ALS, neuronal regeneration and axonal growth may be limited by a hostile environment characterized by extensive gliosis and aberrant remodeling of ECM components [8]. Accordingly, gene ontology analysis of differently expressed genes in the spinal cord of hFUS mice show ECM matrix disorganization and increased expression of proteoglycans [40,44].…”

“…Due to its properties, the protein has been implicated in the brosis of many organs, such as kidney, liver, lung and heart [22]. In neurodegenerative conditions, including ALS, an interplay between brosis and in ammation in different organs and tissues is an emerging concept that relies on data showing alterations of the ECM components and remodeling enzymes, increase in brotic markers as TGF-, as well as in pro brotic genes [8,12,29]. Hence, the comprehension of the elements responsible for the in ammatory and brotic pathways appears to be crucial to dissect novel aspects contributing to the pathology of ALS.…”

S100A4 in the Physiology and Pathology of the Central and Peripheral Nervous System

“…Indeed, S100A4 was found to be significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic superoxide dismutase 1 (SOD1)-G93A animal model and in activated primary microglia [ 34 ]. The overexpression of S100A4 on activated glial cells found in ALS rodent models, together with the increase of vimentin and α-smooth muscular actin in the affected regions, suggested that in addition to its well-known functions in regulating inflammation and cell motility, S100A4 participates in the induction of reactive gliosis and in the formation of the so-called “glial scar” [ 61 ]. This glial response characterizes ALS-affected tissues and results from the massive migration of astrocytes and microglia toward the site of injury [ 62 , 63 ].…”