transforming-growth-factor-beta and Brain-Diseases

Neurotrophic factors (NTFs) play an important role in maintaining homeostasis of the central nervous system (CNS) by regulating the survival, differentiation, maturation, and development of neurons and by participating in the regeneration of damaged tissues. Disturbances in the level and functioning of NTFs can lead to many diseases of the nervous system, including degenerative diseases, mental diseases, and neurodevelopmental disorders. Each CNS disease is characterized by a unique pathomechanism, however, the involvement of certain processes in its etiology is common, such as neuroinflammation, dysregulation of NTFs levels, or mitochondrial dysfunction. It has been shown that NTFs can control the activation of glial cells by directing them toward a neuroprotective and anti-inflammatory phenotype and activating signaling pathways responsible for neuronal survival. In this review, our goal is to outline the current state of knowledge about the processes affected by NTFs, the crosstalk between NTFs, mitochondria, and the nervous and immune systems, leading to the inhibition of neuroinflammation and oxidative stress, and thus the inhibition of the development and progression of CNS disorders.

Topics: Brain Diseases; Central Nervous System Diseases; Humans; Nerve Growth Factors; Neuroglia; Neuroinflammatory Diseases; Neurons; Transforming Growth Factor beta

Advances in our understanding of fundamental biological processes can be made by the analysis of defects manifested in inherited diseases. The genes responsible for these genetic syndromes often encode proteins that act at critical points of the pathways that control biological processes such as cell proliferation, cell-cell communication, cellular differentiation, and cell death. This approach has lead to the discovery of novel gene products and/or biochemical pathways involved in disease, genes that in turn play a fundamental role in normal biological processes. This forward genetic approach, focusing on Mendelian disorders of vascular anomalies, has been particularly fruitful for the study of genetic regulation of angiogenesis. This review summarizes the ongoing saga of two genetic syndromes involving disruption of normal vascular morphogenesis. Each inherited disorder involves the focal development of a distinct vascular anomaly. In hereditary hemorrhagic telangiectasia (HHT), the hallmark vascular lesion is termed an arteriovenous malformation, which involves the direct communication of an artery with a vein (arteriovenous shunt), without an intervening capillary bed. For cerebral cavernous malformations (CCM), the lesions are grossly-dilated, closely-packed, capillary-like sinusoidal chambers. The autosomal dominant mode of inheritance of each of these distinct syndromes suggested that the underlying genes might regulate critical aspects of vascular morphogenesis. Emerging but intriguing tales are being told by the genes (and their protein products) mutated in these disorders.

Topics: Activin Receptors, Type I; Activin Receptors, Type II; Amino Acid Motifs; Animals; Antigens, CD; Blood Vessels; Brain Diseases; Cell Adhesion; Cell Communication; Cell Division; Cytoskeleton; Endoglin; Genes, Dominant; Humans; Integrins; KRIT1 Protein; Mice; Mice, Knockout; Microtubule-Associated Proteins; Models, Biological; Mutation; Neovascularization, Pathologic; Protein Structure, Tertiary; Proto-Oncogene Proteins; Receptors, Cell Surface; Signal Transduction; Syndrome; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Astrocytes are involved in multiple brain functions in physiological conditions, participating in neuronal development, synaptic activity and homeostatic control of the extracellular environment. They also actively participate in the processes triggered by brain injuries, aimed at limiting and repairing brain damages. Purines may play a significant role in the pathophysiology of numerous acute and chronic disorders of the central nervous system (CNS). Astrocytes are the main source of cerebral purines. They release either adenine-based purines, e.g. adenosine and adenosine triphosphate, or guanine-based purines, e.g. guanosine and guanosine triphosphate, in physiological conditions and release even more of these purines in pathological conditions. Astrocytes express several receptor subtypes of P1 and P2 types for adenine-based purines. Receptors for guanine-based purines are being characterised. Specific ecto-enzymes such as nucleotidases, adenosine deaminase and, likely, purine nucleoside phosphorylase, metabolise both adenine- and guanine-based purines after release from astrocytes. This regulates the effects of nucleotides and nucleosides by reducing their interaction with specific membrane binding sites. Adenine-based nucleotides stimulate astrocyte proliferation by a P2-mediated increase in intracellular [Ca2+] and isoprenylated proteins. Adenosine also, via A2 receptors, may stimulate astrocyte proliferation, but mostly, via A1 and/or A3 receptors, inhibits astrocyte proliferation, thus controlling the excessive reactive astrogliosis triggered by P2 receptors. The activation of A1 receptors also stimulates astrocytes to produce trophic factors, such as nerve growth factor, S100beta protein and transforming growth factor beta, which contribute to protect neurons against injuries. Guanosine stimulates the output of adenine-based purines from astrocytes and in addition it directly triggers these cells to proliferate and to produce large amount of neuroprotective factors. These data indicate that adenine- and guanine-based purines released in large amounts from injured or dying cells of CNS may act as signals to initiate brain repair mechanisms widely involving astrocytes.

Topics: Adenine; Adenosine Triphosphate; Animals; Astrocytes; Brain; Brain Diseases; Brain Injuries; Cell Division; Chickens; Energy Metabolism; Extracellular Space; Guanine; Guanosine Triphosphate; Humans; Ion Transport; Mice; Nerve Growth Factors; Nerve Tissue Proteins; Neuroprotective Agents; Nucleosides; Nucleotides; Rats; Receptors, Purinergic P1; Receptors, Purinergic P2; Signal Transduction; Transforming Growth Factor beta

1. The identification of cytokine genes expressed in the central nervous system is critical to understanding the immune network in various diseases of brain, such as infection, degeneration, and malignancy. 2. Expression of cytokine genes in human astrocytoma cell lines and in fresh brain specimens was studied by the reverse-transcribed/polymerase chain reaction method. 3. The correlation between clinical malignancy and cytokine gene expression within malignant glioma was examined, especially regarding the relevancy of inhibitory cytokines, such as transforming growth factor-beta and interleukin-10.

Topics: Animals; Astrocytoma; Brain; Brain Diseases; Brain Neoplasms; Cytokines; Humans; Interleukin-10; Neurodegenerative Diseases; Transforming Growth Factor beta; Tumor Cells, Cultured

TGF-beta 1 mRNA and protein were recently found to increase in animal brains after experimental lesions that cause local deafferentation or neuron death. Elevations of TGF-beta 1 mRNA after lesions are prominent in microglia but are also observed in neurons and astrocytes. Moreover, TGF-beta 1 mRNA autoinduces its own mRNA in the brain. These responses provide models for studying the increases of TGF-beta 1 protein observed in beta A/amyloid-containing extracellular plaques of Alzheimer's disease (AD) and Down's syndrome (DS) and in brain cells of AIDS victims. Involvement of TGF-beta 1 in these human brain disorders is discussed in relation to the potent effects of TGF-beta 1 on wound healing and inflammatory responses in peripheral tissues. We hypothesize that TGF-beta 1 and possibly other TGF-beta peptides have organizing roles in responses to neurodegeneration and brain injury that are similar to those observed in non-neural tissues. Work from many laboratories has shown that activities of TGF-beta peptides on brain cells include chemotaxis, modification of extracellular matrix, and regulation of cytoskeletal gene expression and of neurotrophins. Similar activities of the TGF-beta's are well established in other tissues.

Topics: Animals; Brain Diseases; Humans; Immunity; Inflammation; Nerve Degeneration; RNA, Messenger; Transforming Growth Factor beta

Neurocysticercosis (NCC) caused by the helminth Taenia solium is the most common parasitic infection of the human central nervous system (CNS) worldwide. Because clinical symptoms are associated with localized immunological responses in the brain, characterization of these responses are pivotal for understanding the pathogenesis of cysticercosis. Immunohistochemical analysis of brain specimens from several patients with cysticercosis revealed at least four types of immune responses, including: (i) an antibody response (IgM + plasma cells), (ii) a predominant NK response, (iii) an infiltrate with abundant macrophages and granulocytes, and (iv) an intense infiltrate with a predominance of macrophages and T cells. The intensity and type of immunity appeared to be associated somewhat with the parasite's viability and anatomical location. In most of the lesions, cell mediated responses were evident and proinflammatory cytokines including IL12 predominated. Moreover, IL4 was undetectable in the immune infiltrates. Thus, the CNS response to this helminth, unlike the systemic response, is predominately Th1-like.

Topics: Adult; Antigens, Helminth; Biopsy; Brain Chemistry; Brain Diseases; Cysticercosis; Female; Granulocytes; Humans; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-2; Interleukin-4; Interleukin-6; Macrophages; Male; Meninges; Middle Aged; T-Lymphocytes; Th1 Cells; Th2 Cells; Transforming Growth Factor beta