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

  • Abstract
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Abstract

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.

Keywords:

Extracellular matrix, Fibronectin, Integrin, Extrasynaptic transmission, Neuron-glia networks

Article Outline

  1. Introduction
  2. Molecular architecture of the ECM and extrasynaptic transmission in normal brain
  3. Molecular structure and biological significance of fibronectin and integrin receptors
  4. Neuroprotective effect of fibronectin and its molecular mechanism
  5. Fibronectin is an age-related ECM component and regulator of extrasynaptic transmission
  6. Roles of fibronectin and extrasynaptic transmission in neurodegenerative pathogenesis
  7. Conclusions
  8. References

Abstract

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.

Keywords:

Extracellular matrix, Fibronectin, Integrin, Extrasynaptic transmission, Neuron-glia networks

1. Introduction

For two decades, a considerable amount of evidence has demonstrated that there exist two major modes of neural communication in the neuron-glia network of the central nervous system (CNS), the synaptic transmission (or wiring transmission) and the extrasynaptic transmission.1,2 The former is known as the fact that the synaptically evoked astrocytes produce the elevated Ca2+ signals in the cytosol, which can trigger the release of gliotransmitters and play neuromodulatory and information-integrative roles in neuronal activity, synaptic transmission, and plasticity.3 The latter refers to the findings that a wide variety of bioactive substances, such as neurotransmitters and neuromodulators secreted by neurons and neuroglia are released or leaked into the extracellular space (ECS), and perform bidirectional signal communications between them in the form of molecular diffusion and tissue fluid flows, and then play slow and sustained neuromodulatory action on neuonal activity.2 This kind of communication is variously named as “nonsynaptic or extrasynaptic transmission,” “volume or diffusion transmission,” “tissue channel,” or “intercellular channel.”4,5Measurements of extrasynaptic transmission are determined by the diffusion properties, such as specific diffusion parameters and structural composition of extracellular matrix (ECM) in the ECS.6 Fibronectin, being a ubiquitous ECM component, plays critical roles in extrasynaptic transmission by regulating matrix structure, such as specific binding to growth factors or clearance of degraded products, and directing cell behaviors.7,8However, in the context of brain aging, a new insight needs to be provided into molecular and functional implications of fibronectin matrix and its regulatory role in extrasynaptic transmission, even in defining drug delivery within the normal and aged CNS.

It’s well known that aging is accompanied by stereotypical structural and neurophysiological changes in the brain and variable degrees of functional decline, especially in neural transmission and ECM alterations,1which may contribute to pathogenesis of neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Previous data have shown that synaptic transmission in the aged brain has acquired extensive and in-depth studies in the changes of neurotransmitters and neural integration, such as in losses of synapses and neurons, and disruption in gray or white matter integrity.9,10 However, the age-related changes in ECM and its extrasynaptic transmission have long been given less academic attention because of the difficult and variable technical approaches and the traditional conception about lesser neural function of ECM, about which a lot of data came from Eva Syková, Academy of Sciences of the Czech Republic. Concurrently, although fibronectin is known as a conventional ECM macromolecule, its uncovered action mechanism underlying neuronal prosurvival may bring about a greater understanding of developing therapeutic interventions for some geriatric neurological conditions.

In this review, we provide an updated overview of researches on age-related alteration of ECM and explore the potential neuroprotective mechanism of fibronectin. We begin with a brief description of the normal ECM molecular composition and diffusion parameters, with a focus on the molecular structure, action mechanism, and biological significance of fibronectin and integrin receptors to deeply analyze the structural and functional properties of ECM. Then, we include a discussion of negative effects of aging on ECM and its extrasynaptic transmission. Finally, the molecular basis and therapeutic implications of fibronectin in the age-related alterations in extrasynaptic transmission will be described.

2. Molecular architecture of the ECM and extrasynaptic transmission in normal brain

The ECM, as the basic structure of ECS, is a fibrillar meshwork consisting of many long-chain polyelectrolytes, such as glycoproteins (e.g., fibronectin, tenascins, laminin, collagen IV, thrombospondin, and so forth11), glycosaminoglycans (e.g., hyaluronate), and proteoglycans (e.g., chondroitin sulfate and heparin sulfate) either tethered or untethered to cellular surfaces,12,13 all of which respectively play a critical role in modulating the ECS microenvironment and extrasynaptic transmission by diffusion barrier, molecular interaction, and ligand-receptor binding, and so forth in addition to their mechanical strength and elastic properties given to tissues. Among these macromolecules, although heparan sulfate proteoglycan is a prominent component of ECM in the brain, various adhesion molecules, for example, fibronectin, tenascin, and laminin14,15 have also been demonstrated to be important components of the ECM that persists in the adult brain, with fibronectin being predominant only in perineuronal nets and mainly participating in architecture and function of neuron-glia network.16,17 These molecules are produced by both neurons and neuroglia and execute a wide variety of biological functions, including storage and binding of neuroactive substances (e.g., growth factors11), cell anchorage, control of cell proliferation and differentiation,18 and synthesis and remodeling of the ECM.11Meanwhile, the ECM composition and density vary with brain regions,19,20 reflecting the heterogenicity of ECM action and the anisotropy of extrasynaptic transmission, which may provide a hint for unveiling the mechanism of brain aging and age-related pathological processes. For more information about the ECM physiological properties, please refer to a latest systematic review by Syková and Nicholson.6

The extrasynaptic transmission is generally divided into four principal types in the normal CNS5,6: (1) the intercellular short-distance transmission, (2) the transmission associated with cerebrospinal fluid, (3) the long-distance transmission along nerve fibers, and (4) the long-distance transmission around blood vessels. The latter two transmissions of (3) and (4) are involved in faster and longer signal transmission that can happen between brain nuclei, cerebral areas, and even cerebral hemispheres, including the movement of various bioactive substances, such as ions, neuropeptides, neurohormones, and metabolites, as well as the hematologic exudates, such as cell adhesion molecules, growth factors, and inflammatory molecules under pathological conditions. The diffusion capability of extrasynaptic transmission in the ECS is determined by three specific diffusion parameters6: (1) ECS volume fraction alpha (α) (α=ECS volume/total tissue volume), which can be reduced because of the cerebral atrophy in the elderly, especially with AD17; (2) tortuosity lambda (λ) (λ2=free/apparent diffusion coefficient), reflecting the condition of diffusion barriers, such as fibrillar fibronectin architecture and other ECM macromolecules, fine neural processes, charged molecules, and degrading enzymes; and (3) nonspecific cellular uptake (k+), indicating the degree of cell swelling. These diffusion parameters differ in various brain regions, showing inhomogeneous diffusion background in the brain and are easily affected by pathological factors, such as age-related ECS shrinkage and ECM stiffness,21 cell swelling, and glial remodeling, and so forth. These diffusion parameters modulate extrasynaptic transmission, neuronal signaling, and neuron-glia communication.

In the CNS, the fibronectin, an important structural molecule of ECM, is produced and secreted by neuroglial cells and endothelial cells and forms a meshwork close to neural cell surfaces to support and control the extrasynaptic transmission. Some evidence shows that in addition to supportive and adhesional roles, fibronectin matrix can act as a storage depot for a variety of growth factors and indirectly exerts a neuroprotective effect on neural cells,11,22 the mechanism of which may be related to the interaction between fibronectin or integrins and many neurotrophic factors, such as insulin-like growth factor-1 (IGF-1) (as shown below), and may contribute to a comprehensive understanding of the outcome of extrasynaptic transmission and the functional role of neuron-glia networks, including molecular pathogenesis and potential therapeutic approach for neurodegenerative disorders.

3. Molecular structure and biological significance of fibronectin and integrin receptors

Fibronectin is a heterodimeric glycoprotein encoded by a single gene and disulfide bonded at its carboxyl terminal, each unit of which contains three types of repeats (Type I, II, or III repeat) and constitute multiple domains: the middle one is Arg-Leu-Asp (RGD) motif that can bind to integrin and nonintegrin receptors, and the one at carboxyl terminal is heparin binding site (containing a variable sequence of V zone) that has a higher expression level in the embryonic period and a lower one in the elderly, displaying a neuroprotective effect.23 Fibronectin has a wide variety of cell sources, such as astrocytes,24 epithelial cells, fibroblasts, and mesenchymal cells,25 and so forth, and participates in cell adhesion, proliferation and differentiation, epithelial tissue repair, immune regulation and neural regeneration, and other physiological activities.

Integrins are a family of transmembrane glycoprotein receptors and their molecular structure is composed of one alpha (α) and one beta (β) subunits binding to each other by noncovalent bonds. They can recognize and bind to many ECM proteins, including fibronectin, and also bind to other types of receptors (e.g., receptors for growth factors) on cell surface, to exert dual functions of cell adhesion and signal transduction. At present, it is well established that there are 19 α and eight β subunits that combine to form at least 25 different integrin receptors in mammals.23,26 Most α subunits only bind to one β subunit and sometimes to multiple β subunits, such as α4β1,7, α6β1,4, αvβ1,3,5,6,8, and so forth. Both α and β subunits have one large extracellular region (binding to RGD of matrix molecule), one transmembrane region, and one small intracellular region (having no catalytic effect). Integrins are functionally mainly divided into three subfamilies: β1 integrin (i.e., very late antigen), β2 integrin (i.e., leukocyte integrin), and αv integrin, with β3 integrin (i.e., cell adhesion integrin) also given more focus recently. Each integrin has its own ECM ligand and mediates bidirectional signal transduction, that is, binding of an integrin to its ligand can activate intracellular signaling events, which in turn affect the affinity of ligand and integrin. In most cases, integrins can combine with neighboring receptor (i.e., counter receptor) on cell surface to form integrin receptor complex or receptor mosaics,27which can transactivate intracellular signaling and perform ligand-simulating biological effects. This characteristic of multimolecular interaction on cell surface reveals the diversity and complexity in cell functional regulation of integrins.28

The contributions of fibronectin and integrins to the extrasynaptic transmission in the brain are embodied in several aspects: (1) the fibrillar network closely surrounding neural cells is accumulated with a noncollagen ECM component fibronectin and synthesized by many cell types, such as astrocytes, endothelial cells, fibroblasts, and myoblasts. This network can store the bioactive substances and support the biomolecular flows to form dynamic pathways in some directions and then to guide and facilitate or arrest the extrasynaptic transmission in the adult brain.2,8 Alternatively, this poriferous architecture offers a matrical platform contributing to cell-matrix or cell-cell information communication and functional regulation of neuron-glia network7,25; (2) the mediative effect of integrins in fibronectin neurotrophic signal transduction: fibronectin-integrins-growth factor receptor-signal transduction-gene and protein expression, by which the altered extrasynaptic transmission may modulate the functional outputs of cells as a compensatory effect for synaptic transmission with a predominate nature29,30; (3) the energy gradients, such as concentration gradient, temperature gradient, and pressure gradient, being drivers for diffusion of various bioactive substances and displaying the properties of slower diffusion, less safety, less spatial constraint, and wider diffusion range that allows the reach of a large number of targets.2

Therefore, the expression level of fibronectin can directly influence diffusion and permeability of various neuroactive substances and may be facilitated and strengthened in some directions to meet the homeostasis changes. These preferential extrasynaptic transmission channels are believed to play an important role in intercellular short distance and perineurofiber long distance neurotransmitter diffusion and may become pathological source or used as a possible intervention approach for neurodegenerative diseases, such as PD.31 In geriatric patients, the significant alterations in volume, tortuosity, and anisotropy of brain ECS seriously affect permeability of extrasynaptic communication, and bring about synapse-transmitter leakage and transmitter-receptor mismatches31,32 that give rise to abnormal accumulation and diffusion of neuroactive substances. This mechanism contributes to the explanation for pathogenesis of PD or other neurodegenerative diseases and provides a pharmacological research target for ameliorating neuroinformatic transmission, cell migration, and drug delivery and treatment.2

4. Neuroprotective effect of fibronectin and its molecular mechanism

Fibronectin acts as a pleiotropic regulatory protein that has a critical role in promoting cell growth and differentiation,33,34 which has been extensively demonstrated in multiple cell sources. In the cerebrovascular endothelial cells, fibronectin mediates the mitogen-activated protein kinase (MAPK) signaling pathway via α5β1 and αvβ3 receptors and obviously promotes cell survival and proliferation.35 In the lipopolysaccharide-induced liver cell injury, fibronectin plays a role of cell protection and functional recovery.36 And in the brain, fibronectin plays a neurotrophic and anti-inflammatory role and promotes the growth and survival of neurons.33,37 It has been confirmed that the fibronectin Type III (Fibronectin 3) modules of neural cell adhesion molecule are involved in the direct interaction between neural cell adhesion molecule and fibroblast growth factor receptor in dopaminergic (DA), hippocampal, and cortical neurons38 and then activate the MAPK and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signal transduction pathways and induce neuronal differentiation and proliferation in vitro.39 The administration of synthetic fibronectin peptide V can increase the survival of neural grafts in mesencephal substantia nigra in vivo and ameliorate the motion behavior of PD animals, suggesting the antiapoptotic effect of fibronectin.40 In the microglia, fibronectin can activate the PI3K-Akt and mitogen-activated protein kinase kinase-extracellular signal-regulated kinase-signaling pathways, enhance the expression levels of neurotrophic factors,41 and alleviate the release of proinflammatory factor interleukin 1, all of which contribute to neural repair and neuronal survival.42,43 In the fibronectin knockout mice, the volume of traumatic brain injury is significantly increased and more apoptotic cell death is observed, but with intravenous injection of fibronectin before the injury, the restoration of neural deficits can be seen in the fibronectin-deficient mice, indicating that fibronectin may play neuroprotective role in the repair of brain traumatic injury and may be a novel molecular target for therapeutic interventions.44 In the studies on spinal cord injury45 and cultured oligodendrocytes,46,47 it is demonstrated that fibronectin has a powerful enhancing effect on axon growth; and in a study on traumatically injured mouse brain, fibronectin can promote the survival and migration of transplanted primary neural stem cells, suggesting a possible tool of cell therapy for traumatic brain injury.48 Taken together, researches on neuroprotective role of fibronectin are expected to develop a new therapeutic approach for neurodegenerative diseases (e.g., AD and PD). Beyond that, fibronectin could in turn become an important pharmacological tool for the study of specific functional aspects (e.g., neuroprotection and neuromodulation, and so forth) of extrasynaptic transmission and neuron-glia networks.

The neuroprotective mechanism of fibronectin is mediated by both integrins and growth factor receptors. Binding of the three major subfamilies integrins (β1, β2, and αv) to ECM proteins and related counter receptors can trigger a great deal of intracellular structural alterations and signaling cascades, including the assembly of multimolecular complexes onto the cytoplasmic integrin tails to engage and organize the cytoskeleton and the activation of signaling pathways to modulate gene expression and functional outcomes. In this course, the integrin-mediated signaling can crosstalk with growth factor-mediated signaling at various levels.11Furthermore, although integrins functionally identify fibronectin ligand to play a cell adhesion role, they can also combine growth factor receptors to regulate or mimic functional activities of growth factors via receptor transactivation and intracellular signaling events. In the CNS, β1 and αv are extensively expressed in several cell types, such as neurons, glial cells, and epithelial cells, and so forth, and β2 is only expressed in microglia. α5β1, α3β1, and α4β1 integrins can bind to fibronectin29,49 to exert the effects of growth promotion and functional regulation in neural cells50,51 and cerebrovascular endothelial cells.35 It has been demonstrated that β1 and αv integrins can transactivate a variety of receptors for growth factors and mimic the somatotrophic or neuroprotective effect of growth factors, such as fibroblast growth factor, IGF-1, and glial cell line-derived neurotrophic factor, and so forth.11,52,53 In the DA neurons of substantia nigra that has high level of constitutive expression of IGF-1 receptor (IGF-1R), β1 integrin (e.g., α3,4,5β1) can activate IGF-1R/PI3K/Akt signaling pathway other than MAPK/-regulated kinase pathway by IGF-1-independent transactivation of IGF-1R and then produce an enhanced IGF-like neurotrophism in the degenerated DA neurons.54,55 The analogous mechanism also often exists in other cell types. For example, in the pancreatic cancer cells, the fibronectin, being abundant in pancreatic tumor, engages IGF-IR to inhibit the cell death by stimulating complex formation between β3 integrin and protein-tyrosine phosphatase SHP-2, which can prevent SHP-2 from dephosphorylating IGF-IR and then result in sustained phosphorylation of IGF-IR leading to the downstream activation of Akt kinase and the inhibition of apoptosis through upregulation of antiapoptotic factor (Bcl).33 In the prostate cancer, β1 integrin expression is required for IGF-IR-mediated cancer cell proliferation and anchorage-independent growth,34 which can bring about the extended activation of IGF-1R and amplify the biological effects of IGF-1.56 All above evidence suggests that the fibronectin-related neuroprotection could be entirely mediated by IGF-IR independently of IGF-1, and fibronectin and IGF-IR might be chosen as key targets for pharmaceutical development of the prosurvival effects of ECM proteins and growth factors.

5. Fibronectin is an age-related ECM component and regulator of extrasynaptic transmission

During aging, along with changes in protein synthesis in the brain, the expression and function of individual ECM proteins could either increase or decrease, and the rates of change across the lifespan could also differ among proteins. In the following section, the age-related alterations of ECM, fibronectin, and integrins are analyzed to unveil the effect of aging on the structure and functioning of extrasynaptic transmission involving the profile of fibronectin neurotrophic signal pathway (interaction with neurotrophic factors).

5.1. Reduced amount of ECM during aging

Traditionally, the ECM displays a simple scaffold functioning as a mechanical support for cells, but its interactions with cells can trigger a variety of signaling events via integrins, which provide a molecular bridge between the external environment of the cell and its internal molecule reaction.57,58 The technique of single-particle tracking and fluorescence recovery after photobleaching confirmed59 that there is a net-like ECM wrapping the surface of rat primary neurons, which acts as lateral diffusion barriers for a type of glutamate receptors, and when the ECM was enzymatically removed, the extrasynaptic receptor diffusion and the exchange of synaptic receptors were increased, suggesting that the ECM hindrance differently affects cell function, for example, synaptic transmission and plasticity in an aged matrix. In aging brain, a substantial structural decrease and a functional decline of the ECM have been extensively demonstrated6,16,17,60,61to exert critical effects on extrasynaptic transmission and cell functional regulation as summarized in the following aspects: (1) A reduced amount of ECM and shrinkage of ECS result in a significantly lower ECS volume fraction alpha and nonspecific uptake of k+ and a higher ECS tortuosity lambda, reflecting a decreased diffusion and a larger accumulation of various neurotransmitters and neuromodulators and a reduced clearance of neurotoxins such as; degraded products or metabolites, all of which can mainly bring about abnormal functions or illnesses of the aging brain17; (2) The storage capacity of matrix for various neural growth factors, such as IGF, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor11,30 diminishes during aging because of degradation of various ECM proteins, reflecting the decline of ECM’s neurotrophic function for neurons and glia, and the resultant neuronal atrophy,61 which is possibly one of the underlying mechanisms of neurodegenerative disorders; (3) The upregulated cathepsins in the aged brain exacerbate the proteolytic degradation process of ECM and the shrinkage of ECS and subsequently result in astrogliosis and microglial activation characteristic of advanced brain aging,62 leading to a Alzheimer brain63or age-related neuronal dysfunction.64 In addition, although some ECM proteins, such as chondroitin sulfate proteoglycans have been commercially manufactured as pharmacological approaches such as joint soother, the development of them for neurotrophic purposes or diagnostic biomarkers of neurodegenerative disorders remains to be performed with potential therapeutic implications in the future.

5.2. Reduced content of fibronectin during aging

The fibronectin composes a fibrillar architecture of ECM and plays a pivotal role in direct movement of ions, cytoplasmic solutes, and neuroactive substances in ECM functioning, that is, neuron-glia networks of the CNS.65 Furthermore, the altered expression level of fibronectin under the influence of various pathological factors, such as aging and neuroinflammatory response can affect neuronal functional outputs.66,67,68 The fluorescence resonance energy transfer in vitro shows21 that the dynamic conformational changes of fibronectin lead to the extension and rigidity of fibronectin structure and the exposure of cryptic sites in fibronectin modules, which can regulate integrin binding, cell signaling, and the ability of cells to construct new matrix fibrils.69 In the aging brain,17 the substantial decrease of fibronectin content in ECM has been demonstrated to result in a smaller ECS, although a partial compensatory role through a decreased diffusion barrier, and contribute to age-related neural deficits and memory loss, the underlying mechanism of which is analyzed as follows: (1) The stretching and unfolding of fibronectin plus stiffness of the ECM affects the storage capacity of ECM for neuroactive substances, the molecular and cellular recognition, and cell-matrix interaction; (2) The dowregulated fibronectin may reduce the combination of integrins to IGF receptor, which can alter IGF signal transduction and then lead to neuronal dysfunctions70; (3) The dowregulated fibronectin as well as laminin is always accompanied by the upregulated glial fibrillary acidic protein expression, which can stimulate the hypertrophy of astrocytes (a source of smaller ECS and higher diffusion barrier) and is known as a proximal cause of neuron atrophy during normal aging.17,71 Therefore, the pharmacological use of fibronectin may be a promising clinical approach to reverse the structural and functional alterations of matrix for the treatment of neurodegenerative disorders.

Integrins, a family of receptors for ECM proteins like fibronectin,29 can also bind to the growth factor receptors as counter receptors to modulate the neuronal activities and synaptic plasticity,59 which are significantly reduced in aging and pathological processes.72,73 A study in vitro shows that cultured adult neurons lack the regenerative ability because of the low levels of growth-promoting molecules and the presence of inhibitory proteoglycans as compared with the young neurons.73 However, when the expression level of α-integrin (a receptor for neurogrowth factor) is increased by gene transfer, the regenerative performance of adult neurons can be restored, suggesting that the decreased level of integrins is associated with aging process. Prolonged dietary restriction could cause an increase in the levels of fibronectin mRNA and protein in the aged rat brain, which may underlies its molecular mechanisms against brain aging and neurodegenerative disorders.74,75The α5β1integrin, a specific receptor for fibronectin, can rescue a neurite outgrowth of NT2N cells induced by fibronectin by using a retroviral vector expressing α5 integrin, suggesting a neuroprotective role of integrins and fibronectin,29,30,76 in addition to their angiogenic effects.77 Taken together, integrins, along with their ligands, play a critical role in age-related neurotrophy and neuroprotection, and neural differentiation and regeneration by cell-matrix signal transduction.37,78,79 However, it’s noteworthy that some integrins, for example, α2β1 and αVβ1 exert neurotoxic effects and facilitate neurodegeneration process in AD.80

6. Roles of fibronectin and extrasynaptic transmission in neurodegenerative pathogenesis

During aging, the reduced content of fibronectin matrix protein and integrins play an important role in microenvironmental remodeling and abnormal neuronal activities. As described above, the neurotrophic mechanism of fibronectin and integrins have been demonstrated to apply to multiple neurodegenerative disorders, such as PD and AD. In a PD brain, the DA synaptic transmission in nigrostriatal pathway is greatly abated or blocked for two reasons: (1) the striatal DA deficit in PD brain because of a decreased DA synthesis of degenerated nigral neurons; (2) the increased diffusion barriers and altered matrix content of extrasynaptic transmission along the nigrostriatal pathway,17,81 which are known as a main pathological change of PD brain because there is evidence that the nigrostriatal DA pathway mainly operates via volume transmission or extrasynaptic transmission, that is, nigral dopamine reaches target cells mostly by dopamine diffusion along concentration gradient of the ECS. Although a downregulated expression of fibronectin in the elderly brain can compensatively reduce diffusion barrier and partly ameliorate DA diffusion, the increased volume fraction is still not reversed.9,82 Therefore, the extrinsic fibronectin could hopefully be developed as a neuroprotective agent to augment fibronectin level in the ECM of aged brain, which not only enhances survival of DA neurons but also maintains a good ECM status for unrestricted diffusion and traffic of DA along the nigrostriatal pathway, especially when synaptic transmission is pathologically blocked.83,84,85 In an AD brain, an accumulation of fibronectin in senile plaques may be caused by a partial response of the activated astrocytes to the presence of amyloid peptide featuring AD pathogenesis because when A-beta amyloid peptide is added to cultured astrocytes, a marked increase in fibronectin production is induced. A role of fibronectin in favoring neurite outgrowth has been demonstrated in vitro.66,86 Furthermore, the plasma level of fibronectin is shown to be an additional diagnostic biomarker of AD,87 reflecting the close relevance of fibronectin to AD pathogenesis. Also, the increased fibronectin level in the cerebrospinal fluid can be used as an important parameter in diagnosing neurodegenerative diseases, for example, amyotrophic lateral sclerosis and multiple sclerosis.88,89 The proneuronal and metabolic effects of fibronectin will be helpful in formulating new therapeutic and diagnostic strategies.

7. Conclusions

Recently, a new model of brain function and a conception of active brain have been established, in which the brain should no longer be regarded as a circuitry of neuronal contacts, but as an integrated network consisting of neurons, glia, and ECM.90 Within this network, fibronectin and other ECM proteins are not only involved in the scaffold architecture of ECM and its diffusion transmission (i.e., extrasynaptic transmission) but also involved in integrin signal transduction to regulate neuronal information processing and synaptic integration and then to elaborate neuromodulatory responses to age-related changes of anisotropic diffusion signaling and transmitter release.91,92 The anisotropy of ECM diffusion makes it possible for extrasynaptic transmission to run in some specific directions or along dynamic and preferential intercellular communication channels, that is, tissue channels. Therefore, fibronectin matrix proteins could be pharmacologically developed as a supplementary agent to reverse the age-related alterations of cell-matrix interaction in the aging brain.

The fibronectin engages its specific molecular domains to combine an integrin receptor and a growth factor receptor into a receptor complex or receptor mosaic27 and then transactivate and mimic the prosurvival effect of this growth factor. For example, fibronectin can bind to and activate both integrin receptors and IGF-1R and then trigger the IGF-1R/PI3K/Akt signaling to facilitate survival of DA neurons.39,41 Therefore, the fibronectin can be used as an endogenous repair protein of ECM to ameliorate brain extracellular microenvironment. Taken together, we should strengthen the research on the functional manipulation of fibronectin in extrasynaptic transmission and neuron-glia networks to tremendously broaden our understanding for the complexity of fibronectin- and integrin-mediated signaling networks and to find out a new and effective approach for diagnosing and treating neurodegenerative disorders.

Acknowledgments

Role of the funding source: This work was supported by a grant ( 2005DKA32400 ) from the National Science and Technology infrastructure platform: Medical and Health Scientific Data Sharing Network, Ministry of Science and Technology, People’s Republic of China.

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  37. Tom, V.J., Doller, C.M., Malouf, A.T., and Silver, J. Astrocyte-associated fibronectin is critical for axonal regeneration in adult white matter. J Neurosci. 2004; 24: 9282–9290
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  56. Legate, K.R. and WickströmSA, Fässler R. Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev. 2009; 23: 397–418


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