transforming-growth-factor-beta and Cognition-Disorders

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

Topics: Animals; Cognition Disorders; Disease Models, Animal; Humans; Hydrocephalus, Normal Pressure; Mice; Subarachnoid Hemorrhage; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor beta (TGF-beta) and Chloride channel-3 (CLC-3) are critical for inflammatory response, cellular proliferation and apoptosis in hippocampus neurons. However, the relationship between CLC-3 and TGF-beta/TGF-beta Receptor II (RII) pathway in diabetic encephalopathy (DE) is unknown. In this study, both diabetes rat model and diabetes cell model were employed to elucidate the mechanisms involved. The increased expressions of CLC-3 and TGF- beta RII with cognitive impairment were observed in diabetic rats. The most obvious reduction on the survival of HT22 cells was at 10 ng/ml or 15 ng/ml TGF- beta stimulation, while the expressions of CLC-3 and TGF-beta RII were significantly increased under high glucose condition. Moreover, the study showed that CLC-3 antagonists had no apparent effect on up-regulated TGF- beta RII, but TGF- beta 1 inhibitors could reduce the up-regulated CLC-3 under high glucose. Results from the present study indicated that CLC-3 and TGF- beta signals might be related to cognitive disorders. The CLC-3 might be modulated by TGF- beta /TGF- beta RII signaling pathway during the development of DE.

Topics: Animals; Blood Glucose; Blotting, Western; Cell Line; Chloride Channels; Cognition Disorders; Diabetes Mellitus, Experimental; Immunohistochemistry; Male; Maze Learning; Mice; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Transforming Growth Factor beta

Stress induces cognitive impairments, which are likely related to the damaged dendritic morphology in the brain. Treatments for stress-induced impairments remain limited because the molecules and pathways underlying these impairments are unknown. Therefore, the aim of this study was to find the potential molecules and pathways related to damage of the dendritic morphology induced by stress. To do this, we detected gene expression, constructed a protein-protein interaction (PPI) network, and analyzed the molecular pathways in the brains of mice exposed to 5-h multimodal stress. The results showed that stress increased plasma corticosterone concentration, decreased cognitive function, damaged dendritic morphologies, and altered APBB1, CLSTN1, KCNA4, NOTCH3, PLAU, RPS6KA1, SYP, TGFB1, KCNA1, NTRK3, and SNCA expression in the brains of mice. Further analyses found that the abnormal expressions of CLSTN1, PLAU, NOTCH3, and TGFB1 induced by stress were related to alterations in the dendritic morphology. These four genes demonstrated interactions with 55 other genes, and configured a closed PPI network. Molecular pathway analysis use the Database for Annotation, Visualization, and Integrated Discovery (DAVID), specifically the gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG), each identified three pathways that were significantly enriched in the gene list of the PPI network, with genes belonging to the Notch and transforming growth factor-beta (TGF-B) signaling pathways being the most enriched. Our results suggest that TGFB1, PLAU, NOTCH3, and CLSTN1 may be related to the alterations in dendritic morphology induced by stress, and imply that the Notch and TGF-B signaling pathways may be involved.

Topics: Animals; Behavior, Animal; Cognition Disorders; Corticosterone; Dendrites; Gene Expression; Gene Ontology; Metabolic Networks and Pathways; Mice; Mice, Inbred BALB C; Protein Interaction Maps; Receptors, Notch; Signal Transduction; Stress, Psychological; Transforming Growth Factor beta

Although postoperative cognitive dysfunction (POCD) is relatively common in elderly patients who have undergone major surgery, the mechanisms underlying this postoperative complication are unclear. Previously, we have investigated the role of cytokine-mediated hippocampal inflammation in the development of POCD in a rat model. Here, we sought to determine in mice the role of cytokine interleukin17A (IL17A) in POCD and to characterize the associated signaling pathways. Old mice underwent hepatectomy surgery in the presence or absence of IL17A monoclonal antibody, and cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimer's disease (AD) were assessed. We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, β-amyloid1-42 (Aβ1-42) production, upregulation of transforming growth factor-β (TGFβ), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus. Surgery-induced changes in cognitive dysfunction and changes in Aβ1-42 and TGFβ/Smad signaling were prevented by the administration of IL17A monoclonal antibody. In addition, IL17A-stimulated TGFβ/Smad activation and Aβ1-42 expression were reversed by IL17A receptor small interfering RNA and a TGFβ receptor inhibitor in cultured astrocytes. Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGFβ/Smad pathway dependent Aβ1-42 accumulation in old subjects. These changes likely contribute to the cognitive decline seen in POCD.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antibodies, Monoclonal; Astrocytes; Biomarkers; Cognition Disorders; Cytokines; Disease Models, Animal; Hepatectomy; Hippocampus; Interleukin-17; Male; Maze Learning; Memory, Short-Term; Mice; Phosphorylation; Postoperative Complications; Signal Transduction; Smad Proteins; Spatial Memory; Transforming Growth Factor beta

Glutamatergic neurotransmission has been implicated in mechanisms of alcohol-induced neurodegeneration and cognitive impairment, but the underlying mechanism remains unknown. Here, we examined whether the group II metabotropic glutamate receptor agonist LY379268 prevents neuronal death and learning deficits in a rat model of binge-like exposure to alcohol.. Following 4-day binge alcohol exposure concurrent with LY379268 or vehicle treatment, Fluoro-Jade B and transforming growth factor-beta (TGF-beta) staining were carried out, and reversal learning in the Morris water maze was assessed.. Fluoro-Jade B staining indicating neurodegeneration was most extensive in the ventral hippocampus and the entorhinal cortex (EC). LY379268 was potently neuroprotective in the EC but not in the dentate gyrus of the hippocampus. In parallel, binge alcohol exposure suppressed TGF-beta expression in both the EC and dentate gyrus, whereas LY379268 increased TGF-beta in the EC only. Finally, neuroprotective effects of LY379268 were accompanied by prevention of deficits in spatial reversal learning.. Our data support a neuroprotective role for group II metabotropic glutamate receptor agonists and TGF-beta in alcohol-induced neurodegeneration.

Topics: Amino Acids; Analysis of Variance; Animals; Anxiety; Bridged Bicyclo Compounds, Heterocyclic; Cognition Disorders; Dose-Response Relationship, Drug; Drug Interactions; Ethanol; Fluoresceins; Gene Expression Regulation; Male; Maze Learning; Nerve Degeneration; Organic Chemicals; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Reversal Learning; Transforming Growth Factor beta

Bone marrow cells (BMCs) can increase the number of activated microglias, which play a central role in the inflammatory response in Alzheimer's disease (AD). Senescence-accelerated mouse (SAM) prone 8 (SAMP8) are widely used in various experiments because of cognitive deficits observed with age. In the present study, 4-month-old SAMP8 were reconstituted with BMCs of C57BL/6 mice by intra-bone marrow-bone marrow transplantation (IBM-BMT), which can reconstitute both donor-derived hemopoietic stem cells and mesenchymal stem cells. Three months after IBM-BMT, the impairment of spatial memory in SAMP8 was found to be ameliorated after analyzing the results of the water maze test. Although IL-1beta, IL-6 and iNOS increased and TGF-beta decreased in 7M SAMP8, IL-1beta, IL-6 and iNOS decreased while TGF-beta increased after IBM-BMT by RT-PCR. Moreover, oxidative stress-related heme oxygenase-1 (HO-1) increased in 7M SAMP8, but significantly decreased after IBM-BMT. In conclusion, this is the first report suggesting that the impaired cognitive ability of SAMP8 is ameliorated by IBM-BMT. It seems likely that decreases in IL-1beta, IL-6, iNOS and HO-1 are a result of the development of donor-derived BMCs.

Topics: Aging; Animals; Bone Marrow Transplantation; Brain; Cognition Disorders; Heme Oxygenase-1; Interleukin-1beta; Interleukin-6; Leukocytes, Mononuclear; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide Synthase Type II; Transforming Growth Factor beta