New insights into the altered fibronectin matrix and extrasynaptic transmission in the aging brain †

The extracellular matrix (ECM) is a fibrillar meshwork consisting of many long-chain polyelectrolytes, such as glycoproteins (e.g., fibronectin), glycosaminoglycans, and proteoglycans, all of which fabricate an anisotropic microenvironment that bears dynamic and preferential intercellular communication channels, that is, extrasynaptic transmission. Fibronectin is a ubiquitous ECM component, which accumulates to form poriferous perineuronal nets to regulate matrix organization, such as specific binding to growth factor receptors or clearance of degraded products, and directing cell behaviors, including receptor activation that transduces signals into cells, in addition to its supportive and adhesional roles. Integrins are a family of transmembrane glycoprotein receptors for both ECM proteins like fibronectin and neural growth factors like insulin-like growth factor-1, and the binding of fibronectin to integrins transactivates the intracellular signaling events, such as phosphatidylinositol 3-kinase/protein kinase B pathway to regulate or amplify growth factor-like neuroprotective actions. In the aging brain, the fibronectin, integrins, and other ECM proteins are all downregulated, which brings about the altered structural and functional properties (e.g., neurotransmitter storage, clearance of metabolites, and diffusion parameters) of ECM and extrasynaptic transmission and underlies the molecular mechanism of neurodegenerative disorders. In this article, the neurotrophic mechanism of fibronectin and integrins for pathogenesis of Parkinson’s disease and Alzheimer’s disease is analyzed, involving interaction of integrin and insulin-like growth factor-1 receptor or glial cell line-derived neurotrophic factor receptor, and the potential therapeutic and diagnostic implications of fibronectin are also discussed.