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

Abstract

a b s t r a c tThe 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.

Fibronectin Produced by Cerebral Endothelial and Vascular Smooth Muscle Cells Contributes to Perivascular Extracellular Matrix in Late-Delayed Radiation-Induced Brain Injury

“…Survival is poorer in aged patient subpopulations than younger comparators; however, these findings are confounded by comorbid neurologic and systemic health conditions, tumor progression and treatment regimen. Data regarding the role of fibronectin in the aging brain are conflicting (86–88) and warrant additional study in the context of neurodegenerative diseases generally.…”

Bioinformatic analysis of the human brain extracellular matrix proteome in neurodegenerative disorders

“…It is well known that the ECM is a very challenging sample for proteomics studies (Lindsey et al., 2016; Naba et al., 2015), and consequently, the low amount of identified ECM components with altered expression could be a consequence of the biochemical protocols used for protein extraction and solubilization prior to mass spectrometry analysis. The brain ECM is a meshwork of highly cross‐linked components with an increased amount of high molecular weight macromolecules that are also highly glycosylated (Quirico‐Santos et al., 2010; Wang et al., 2011). Regular solubilization protocols used in most of proteomics‐based studies are better tailored to intracellular proteins.…”

Shaping Up the Tumor Microenvironment With Cellular Fibronectin

“…Regulation of FN splicing depends strictly on tissue type and developmental stage, and it is tightly coupled to the activity of members of the SR protein family [(e.g., SRSF3, SRSF5) reviewed in (107)]. pFN is expressed throughout the entire lifespan of the organism, though declining with age (108)(109)(110). In contrast, cFN expression is elevated during embryonic development but diminishes significantly after birth (111)(112)(113).…”