Extracellular matrix remodelling in neurological diseases.

The neural extracellular matrix (ECM) in the CNS is a dynamic network of proteins and glycans that exists in multiple forms, including perineuronal nets, perisynaptic ECM and periaxonal coats. Together with the diffuse interstitial ECM, these components regulate synaptic stability, plasticity and network excitability. Behavioural studies highlight the crucial roles of ECM in shaping memory engrams and cognitive flexibility, positioning ECM as a promising therapeutic target for cognitive interventions across neurological diseases. ECM remodelling is a shared hallmark across multiple CNS diseases, yet it manifests in condition-specific patterns, from robust scar formation in trauma and stroke to more subtle and broadly distributed, but functionally substantial, ECM changes in chronic neurological disorders. Mechanistically, ECM remodelling is driven by multiple factors, including neuronal activity, neuromodulation and neuroinflammation. Diverse ECM-targeting treatments have shown efficacy in preclinical models of CNS diseases and provide attractive options for further optimization, repositioning and clinical translation. Furthermore, innovative biochemical and imaging technologies are emerging to provide further insight into ECM composition and dynamics, paving the way for novel ECM-targeting therapeutic strategies and biomarkers for diagnosis and monitoring.