transforming-growth-factor-beta and Neurodegenerative-Diseases

As the most abundant cell types in the brain, astrocytes form a tissue-wide signaling network that is responsible for maintaining brain homeostasis and regulating various brain activities. Here, we review some of the essential functions that astrocytes perform in supporting neurons, modulating the immune response, and regulating and maintaining the blood-brain barrier (BBB). Given their importance in brain health, it follows that astrocyte dysfunction has detrimental effects. Indeed, dysfunctional astrocytes are implicated in age-related neuropathology and participate in the onset and progression of neurodegenerative diseases. Here, we review two mechanisms by which astrocytes mediate neuropathology in the aging brain. First, age-associated blood-brain barrier dysfunction (BBBD) causes the hyperactivation of TGFβ signaling in astrocytes, which elicits a pro-inflammatory and epileptogenic phenotype. Over time, BBBD-associated astrocyte dysfunction results in hippocampal and cortical neural hyperexcitability and cognitive deficits. Second, senescent astrocytes accumulate in the brain with age and exhibit a decreased functional capacity and the secretion of senescent-associated secretory phenotype (SASP) factors, which contribute to neuroinflammation and neurotoxicity. Both BBBD and senescence progressively increase during aging and are associated with increased risk of neurodegenerative disease, but the relationship between the two has not yet been established. Thus, we discuss the potential relationship between BBBD, TGFβ hyperactivation, and senescence with respect to astrocytes in the context of aging and disease and identify future areas of investigation in the field.

Topics: Aging; Astrocytes; Blood-Brain Barrier; Cellular Senescence; Humans; Neurodegenerative Diseases; Transforming Growth Factor beta

Advances in human genetics have implicated a growing number of genes in neurodegenerative diseases, providing insight into pathological processes. For Alzheimer disease in particular, genome-wide association studies and gene expression studies have emphasized the pathogenic contributions from microglial cells and motivated studies of microglial function/dysfunction. Here, we summarize recent genetic evidence for microglial involvement in neurodegenerative disease with a focus on Alzheimer disease, for which the evidence is most compelling. To provide context for these genetic discoveries, we discuss how microglia influence brain development and homeostasis, how microglial characteristics change in disease, and which microglial activities likely influence the course of neurodegeneration. In all, we aim to synthesize varied aspects of microglial biology and highlight microglia as possible targets for therapeutic interventions in neurodegenerative disease.

Topics: Aging; Alzheimer Disease; Animals; Brain; Central Nervous System; Complement Pathway, Classical; Gene Expression Regulation; Genetic Predisposition to Disease; Homeostasis; Humans; Macrophages; Microglia; Neurodegenerative Diseases; Plaque, Amyloid; Transforming Growth Factor beta

Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-β, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.

Topics: Aging; Animals; Complement Activation; Disease Progression; Genetic Predisposition to Disease; Genome-Wide Association Study; Gliosis; Humans; Immunity, Innate; Inflammation; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Transgenic; Microglia; Models, Immunological; Neurodegenerative Diseases; Protein Aggregation, Pathological; Receptors, Immunologic; Signal Transduction; Transforming Growth Factor beta

The TGF-β superfamily signaling is involved in a variety of biological processes during embryogenesis and in adult tissue homeostasis. Faulty regulation of the signaling pathway that transduces the TGF-β superfamily signals accordingly leads to a number of ailments, such as cancer and cardiovascular, metabolic, urinary, intestinal, skeletal, and immune diseases. In recent years, a number of studies have elucidated the essential roles of TGF-βs and BMPs during neuronal development in the maintenance of appropriate innervation and neuronal activity. The new advancement implicates significant roles of the aberrant TGF-β superfamily signaling in the pathogenesis of neurological disorders. In this review, we compile a number of reports implicating the deregulation of TGF-β/BMP signaling pathways in the pathogenesis of cognitive and neurodegenerative disorders in animal models and patients. We apologize in advance that the review falls short of providing details of the role of TGF-β/BMP signaling or mechanisms underlying the pathogenesis of neurological disorders. The goal of this article is to reveal a gap in our knowledge regarding the association between TGF-β/BMP signaling pathways and neuronal tissue homeostasis and development and facilitate the research with a potential to develop new therapies for neurological ailments by modulating the pathways.

Topics: Animals; Bone Morphogenetic Proteins; Cognition Disorders; Homeostasis; Humans; Models, Neurological; Nervous System; Neurodegenerative Diseases; Signal Transduction; Transforming Growth Factor beta

The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington's Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF-β signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homologues of genes that cause neurodegenerative disease at the NMJ have resulted in a better understanding of the roles of these proteins in vivo. These studies may shed light on the pathological mechanisms of these diseases, with implications for reduced BMP/TGF-β signaling in ALS, SMA and HD and increased signaling in HSP and MS.

Topics: Animals; Bone Morphogenetic Proteins; Drosophila; Humans; Neurodegenerative Diseases; Neuromuscular Junction; Signal Transduction; Transforming Growth Factor beta

The HtrA family proteins are serine proteases that are involved in important physiological processes, including maintenance of mitochondrial homeostasis, apoptosis and cell signaling. They are involved in the development and progression of several pathological processes such as cancer, neurodegenerative disorders and arthritic diseases.. We present characteristics of the human HtrA1, HtrA2 and HtrA3 proteins, with the stress on their function in apoptosis and in the diseases. We describe regulation of the HtrAs' proteolytic activity, focusing on allosteric interactions of ligands/substrates with the PDZ domains, and make suggestions on how the HtrA proteolytic activity could be modified. Literature cited covers years 1996 - 2010.. An overview of the HtrAs' function/regulation and involvement in diseases (cancer, neurodegenerative disorders, arthritis), and ideas how modulation of their proteolytic activity could be used in therapies.. HtrA2 is the best target for cancer drug development. An increase in the HtrAs' proteolytic activity could be beneficial in cancer treatment, by stimulation of apoptosis, anoikis or necrosis of cancer cells, or by modulation of the TGF-beta signaling cascade; modulation of HtrA activity could be helpful in therapy of neurodegenerative diseases and arthritis.

Topics: Allosteric Regulation; Animals; Anoikis; Antineoplastic Agents; Apoptosis; Arthritis; Drug Design; Enzyme Activation; High-Temperature Requirement A Serine Peptidase 1; High-Temperature Requirement A Serine Peptidase 2; Humans; Ligands; Mitochondrial Proteins; Necrosis; Neoplasms; Neurodegenerative Diseases; PDZ Domains; Serine Endopeptidases; Signal Transduction; Transforming Growth Factor beta

Neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD) afflict growing numbers of people but treatments are not available or ineffective. These diseases are characterized by the loss of specific neuronal populations, the accumulation of protein aggregates inside and sometimes outside neurons, and an activation of immune pathways in the brain. The causes of sporadic forms of AD or PD are not known but it has been postulated that reduced trophic support to neurons together with age dependent increases in cellular stress lead to chronic injury and ultimately the demise of neurons. TGF-betas are neuroprotective factors and organizers of injury responses and as such might have a role in neurodegenerative disease. We review here the evidence mostly from genetically manipulated mice that links the TGF-beta signaling pathway to neuronal phenotypes and neurodegeneration. Although many of these mutant models did not produce overt CNS phenotypes or adult brain were not studied due to embryonic lethality, there is growing support for a role of TGF-beta signaling in neuronal maintenance, function, and degeneration. Future studies will have to determine whether dysregulation of TGF-beta signaling in neurodegenerative diseases is significant and whether this signaling pathway may even be a target for treatment.

Topics: Animals; Animals, Genetically Modified; Disease Models, Animal; Humans; Mice; Neurodegenerative Diseases; Signal Transduction; Transforming Growth Factor beta

Glucocorticoids can prevent or accelerate neurodegeneration in the adult rat hippocampus. To investigate these actions of glucocorticoids, we previously cloned genes from the hippocampus. Adrenalectomy specifically increased glial fibrillary acidic protein and transforming growth factor (TGF)-beta1 mRNAs in the dentate gyrus and these effects were dependent on induced apoptosis. Corticosterone treatment prevented apoptosis, and decreased glial activation and the influx of activated microglia. Since these effects are opposite to injury and neurodegeneration, we propose that they represent adaptive actions of glucocorticoids, preventing cellular defense mechanisms from overshooting. We used adrenalectomy as a model to investigate how adult granule neurons die in vivo and the effects of neurotrophic factors in protecting against apoptosis. Neurotrophin-4/5 and TGF-beta1 protected granule neurons against adrenalectomy-induced apoptosis. Since neurogenesis is also greatly increased in the dentate gyrus following adrenalectomy, we compared the time course of birth and death with glial responses. TGF-beta1 mRNA increased before the detection of dying cells in the dentate gyrus, which was coincident with increased proliferation in the neurogenic zone. Glucocorticoids also increased Ndrg2 mRNA in glia in the neurogenic zone; Ndrg2 is a member of a novel gene family involved in neural differentiation and synapse formation. Therefore, studying the effects of glucocorticoid manipulation on the dentate gyrus is increasing our understanding of how mature neurons die by apoptosis and the role of glia in induced apoptosis and neurogenesis. Discovering how endocrine and inflammatory responses regulate neuron birth and survival is important for developing successful neuron replacement strategies to treat neurodegenerative diseases.

Topics: Adrenalectomy; Animals; Apoptosis; Cloning, Molecular; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Glucocorticoids; Hippocampus; Humans; Nerve Regeneration; Neurodegenerative Diseases; Neuroglia; Proteins; Rats; Time Factors; Transforming Growth Factor beta; Tumor Suppressor Proteins

Transforming growth factors-betas (TGF-betas), a family of multifunctional peptide growth factors, affect cells of the central nervous system (CNS). The three mammalian TGF-beta isoforms, TGF-betas 1, 2 and 3, are expressed in adult human brain. Since neuronal degeneration is a defining feature of CNS degenerative diseases, TGF-beta may be important because it can influence neuronal survival. In vitro TGF-beta promotes survival of rat spinal cord motoneurons and dopaminergic neurons. In addition to direct effects on neuronal survival, TGF-beta treatment of cultured astrocytes induces a reactive phenotype. Thus, TGF-beta may also normalize the extracellular matrix environment in degenerative diseases. The expression of TGF-betas change in response to neuronal injury. TGF-beta 1 expression increases in astrocytes and microglia in animal models of cerebral ischemia, while TGF-beta 2 expression increases in activated astroglial cells in human neurodegenerative diseases. TGF-betas protect neurons from a variety of insults. TGF-beta maintains survival of chick telencephalic neurons made hypoxic by treatment with cyanide and decreases the area of infarction when administered in animal models of cerebral ischemia. In vitro TGF-beta protects neurons from damage induced by treatment with beta-amyloid peptide, FeSO4 (induces production of reactive oxygen species), Ca2+ ionophores, glutamate, glutamate receptor agonists and MPTP (toxic for dopaminergic neurons). TGF-beta maintains mitochondrial potential and Ca2+ homeostasis and inhibits apoptosis in neurons. TGF-beta does not prevent neuronal degeneration in a rat model of Parkinson's disease and has yet to be tested in newly developed transgenic mouse models of Alzheimer's disease. TGF-beta is a potent neuroprotective agent which may affect the pathogenesis of neurodegenerative diseases of the CNS.

Topics: Animals; Disease Models, Animal; Humans; Neurodegenerative Diseases; 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

The Transforming Growth Factor-betas (TGF-beta) are a group of multifunctional proteins whose cellular sites of production and action are widely distributed throughout the body, including the central nervous system (CNS). Within the CNS, various isoforms of TGF-beta are produced by both glial and neural cells. When evaluated in either cell culture or in vivo models, the various isoforms of TGF-beta have been shown to have potent effects on the proliferation, function, or survival of both neurons and all three glial cell types, astrocytes, microglia and oligodendrocytes. TGF-beta has also been shown to play a role in several forms of acute CNS pathology including ischemia, excitotoxicity and several forms of neurodegenerative diseases including multiple sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease.

Topics: AIDS Dementia Complex; Alzheimer Disease; Animals; Astrocytes; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Gene Expression; Humans; Ischemia; Microglia; Multiple Sclerosis; Neurodegenerative Diseases; Oligodendroglia; Parkinson Disease; Transforming Growth Factor beta

Topics: Brain; DNA Methylation; Humans; Inflammation; Microglia; Multiple Sclerosis; Neurodegenerative Diseases; Transforming Growth Factor beta; White Matter

Glaucoma is a neurodegenerative disease that causes irreversible blindness due to loss of retinal ganglion cells (RGCs) and their axons. We previously identified a G661R mutation of ADAMTS10 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif 10) as the disease-causing mutation in a beagle model of glaucoma. ADAMTS10 is a secreted matrix metalloproteinase that belongs to the ADAMTS family which is involved in extracellular matrix (ECM) turnover. Previous studies have shown that ADAMTS10 binds fibrillin microfibrils, promotes their formation, and influences their fibrillin isoform composition. Here, we established a mouse model carrying the G661R mutation of ADAMTS10 (ADAMTS10

Topics: ADAMTS Proteins; Animals; Disease Models, Animal; Fibrillins; Glaucoma; Mice; Mutation; Neurodegenerative Diseases; Optic Nerve; Optic Nerve Diseases; Retinal Ganglion Cells; Transforming Growth Factor beta

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis. Respiratory complications are the main cause of death in ALS. For this reason, initial respiratory status and its decline over disease progression are strong independent predictors of survival. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug that has shown to extend survival. Therefore, both novel molecular biomarkers and treatment strategies are needed. Transforming growth factor-β (TGF-β) family cytokines are important regulators of cell fate affecting both neurogenesis and neurodegeneration. Several studies demonstrate that TGF-β signalling protects neurons from glutamate-mediated excitotoxicity, a recognized mechanism underlying the pathogenesis of various neurodegenerative disorders such as ALS. Recent studies report dysregulations of the TGF-β system as a common feature of neurodegenerative disorders. The upregulation of this system has been linked with ALS progression. We have quantified TGF-β1, TGF-β2 and TGF-β3 serum levels in 23 ALS patients and 12 healthy controls, our preliminary results support the hypothesis that TGF-β3 levels can be a marker disease severity ALS. Further results are necessary to confirm this hypothesis.

Topics: Amyotrophic Lateral Sclerosis; Humans; Neurodegenerative Diseases; Pharmaceutical Preparations; Plasma; Transforming Growth Factor beta; Transforming Growth Factors

Extracellular proTGF-β is covalently linked to "milieu" molecules in the matrix or on cell surfaces and is latent until TGF-β is released by integrins. Here, we show that LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation. Lrrc33

Topics: Animals; Axons; Bone Marrow Transplantation; Brain; Carrier Proteins; Cells, Cultured; Integrins; Kaplan-Meier Estimate; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Mutagenesis, Site-Directed; Nervous System; Neurodegenerative Diseases; Phylogeny; Protein Binding; Protein Precursors; Transforming Growth Factor beta

Transforming growth factor-β (TGF-β) plays an important role in the development and maintenance of embryonic dopaminergic (DA) neurons in the midbrain. To study the function of TGF-β signaling in the adult nigrostriatal system, we generated transgenic mice with reduced TGF-β signaling in mature neurons. These mice display age-related motor deficits and degeneration of the nigrostriatal system. Increasing TGF-β signaling in the substantia nigra through adeno-associated virus expressing a constitutively active type I receptor significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and motor deficits. These results suggest that TGF-β signaling is critical for adult DA neuron survival and that modulating this signaling pathway has therapeutic potential in Parkinson disease.

Topics: Animals; Cell Survival; Gait Disorders, Neurologic; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; MPTP Poisoning; Neostriatum; Neurodegenerative Diseases; Postural Balance; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Substantia Nigra; Transforming Growth Factor beta

Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Apoptosis; Cerebral Cortex; Cluster Analysis; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Humans; Immune Tolerance; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Transgenic; Microglia; Monocytes; Neurodegenerative Diseases; Neurons; Phagocytosis; Phenotype; Plaque, Amyloid; Receptors, Immunologic; Signal Transduction; Superoxide Dismutase-1; Transcriptome; Transforming Growth Factor beta

Transforming growth factor beta (TGF-β) proteins are multifunctional cytokines whose neural functions are increasingly recognized. The machinery of TGF-β signaling, including the serine kinase type transmembrane receptors, is present in the central nervous system. However, the 3 mammalian TGF-β subtypes have distinct distributions in the brain suggesting different neural functions. Evidence of their involvement in the development and plasticity of the nervous system as well as their functions in peripheral organs suggested that they also exhibit neuroprotective functions. Indeed, TGF-β expression is induced following a variety of types of brain tissue injury. The neuroprotective function of TGF-βs is most established following brain ischemia. Damage in experimental animal models of global and focal ischemia was shown to be attenuated by TGF-βs. In addition, support for their neuroprotective actions following trauma, sclerosis multiplex, neurodegenerative diseases, infections, and brain tumors is also accumulating. The review will also describe the potential mechanisms of neuroprotection exerted by TGF-βs including anti-inflammatory, -apoptotic, -excitotoxic actions as well as the promotion of scar formation, angiogenesis, and neuroregeneration. The participation of these mechanisms in the neuroprotective effects of TGF-βs during different brain lesions will also be discussed.

Topics: Animals; Apoptosis; Brain Neoplasms; Encephalomyelitis, Autoimmune, Experimental; Humans; Nerve Regeneration; Neurodegenerative Diseases; Neuroprotective Agents; Signal Transduction; Transforming Growth Factor beta

Transforming growth factor beta (TGF-beta), a pleiotropic cytokine, regulates a diverse range of cellular responses, such as proliferation, differentiation, migration, and apoptosis. Recent studies indicate that disruption of TGF-beta signaling due to the transcriptional dysregulation of its receptor is associated with polyglutamine-induced motor neuron damage in spinal and bulbar muscular atrophy. Moreover, a single-nucleotide polymorphism (SNP) in the promoter region of ZNF512B, a putative regulator of TGF-beta signaling, is shown to be associated with susceptibility to amyotrophic lateral sclerosis. Signal transduction by BMP, a member of the TGF-beta super family, is decreased in a fly model of spinal muscular atrophy, while the abnormal activation of this signaling has been reported in animal models of hereditary spastic paraplegia. These findings support the hypothesis that the disruption of TGF-beta signaling is an important molecular event in the pathogenesis of motor neuron diseases, and that the modification of this signaling pathway represents a new therapeutic strategy against these devastating disorders.

Topics: Animals; Humans; Mice; Neurodegenerative Diseases; Signal Transduction; Transforming Growth Factor beta

Various chronic neurological diseases are associated with increased expression of transforming growth factor-beta1 (TGF-beta1) in the brain. TGF-beta1 has both neuroprotective and neurodegenerative functions, depending on conditions such as duration and the local and temporal pattern of its expression. Previous transgenic approaches did not enable control for these dynamic aspects. To overcome these limitations, we established a transgenic mouse model with inducible neuron-specific expression of TGF-beta1 based on the tetracycline-regulated gene expression system. TGF-beta1 expression was restricted to the brain where it was particularly pronounced in the neocortex, hippocampus and striatum. Transgene expression was highly sensitive to the presence of doxycycline and completely silenced within 6 days after doxycycline application. After long-term expression, perivascular thioflavin-positive depositions, formed by amyloid fibrils, developed. These depositions persisted even after prolonged silencing of the transgene, indicating an irreversible process. Similarly, strong perivascular apolipoprotein E (ApoE) depositions were found after TGF-beta1 expression and these remained despite TGF-beta1 removal. These in vivo observations suggests that the continuous presence of TGF-beta1 as initial trigger is not necessary for the persistence and development of chronic lesions. Neuroprotective effects were observed after short-term expression of TGF-beta1. Death of striatal neurons induced by 3-nitropropionic acid was markedly reduced after induced TGF-beta1 expression.

Topics: Animals; Anti-Bacterial Agents; Apolipoproteins E; Benzothiazoles; Brain; Doxycycline; Gene Expression Regulation; Gene Silencing; Mice; Mice, Transgenic; Molecular Biology; Nerve Degeneration; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Neurotoxins; Nitro Compounds; Plaque, Amyloid; Propionates; Thiazoles; Transfection; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transgenes