Extracellular matrix remodeling therapeutic strategies to tackle central nervous system diseases

Abstract Neurodegenerative diseases are a global burden due to the increased life expectancy. Neuroinflammation is not only a result of neurodegeneration but a key player in the initiation and onset of it. Due to the inherent complexity of these diseases, there is a need for the development of better treatments, as well as the discovery of new therapeutic targets. In this sense, knowledge about extracellular matrix remodeling after injury in the central nervous system was overseen for a century, but it has blossomed in the last three decades. Nowadays, we possess strong evidence regarding the imbalance, over-synthesis, and changes in the organization of most key components of the extracellular matrix after neuroinflammation and neurodegeneration. Thus, hyaluronic acid, chondroitin sulphate proteoglycans, or fibronectin presented an impairment in their anabolism and catabolism, which could be a cause or a consequence of the inflammatory and degenerative process. Regardless, it is clear that extracellular matrix remodeling plays a pivotal role in the onset and resolution of inflammation-driven neurological disorders by creating a non-permissive niche for self-restoration of the neural homeostasis. Despite being an emerging area of study, extracellular matrix changes have been explored in the last decades in the central nervous system to shed light on their potential as diagnostic markers as well as therapeutic targets. The extracellular matrix fingerprint in diseases such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, or stroke has been described both in preclinical models and in post-mortem clinical samples. Herein, we provided an overview of the state of the art of extracellular matrix components and function in the central nervous system, both under homeostasis and in neurodegeneration. Then, we critically revise the therapeutic efforts targeting the extracellular matrix, aiming to tackle neurodegenerative disorders. Altogether, this review contextualizes the current understanding of extracellular matrix in the central nervous system and its remodeling after neuroinflammation, its role in disease onset and resolution, and how this knowledge is being applied to the development of new therapeutic approaches.