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Open AccessArticle

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

1
Section of Human Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
2
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
3
Biology Group CES-EIA, CES University, Medellín 050021, Colombia
4
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50134 Florence, Italy
5
Bioinformatics Unit, Hospital of Prato, Azienda USL Toscana Centro, 50122 Prato, Italy
6
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK
7
Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1TN, UK
8
Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
9
Neurosurgical Unit, Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, 50134 Florence, Italy
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(17), 6128; https://doi.org/10.3390/ijms21176128
Received: 17 July 2020 / Revised: 7 August 2020 / Accepted: 18 August 2020 / Published: 25 August 2020
TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders. View Full-Text
Keywords: neuroinflammation; Alzheimer’s disease; neurogenesis; human fetal neurons; DNA methylation; nucleus basalis of Meynert; ciliogenesis; NGF; TNFα receptors neuroinflammation; Alzheimer’s disease; neurogenesis; human fetal neurons; DNA methylation; nucleus basalis of Meynert; ciliogenesis; NGF; TNFα receptors
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Guarnieri, G.; Sarchielli, E.; Comeglio, P.; Herrera-Puerta, E.; Piaceri, I.; Nacmias, B.; Benelli, M.; Kelsey, G.; Maggi, M.; Gallina, P.; Vannelli, G.B.; Morelli, A. Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts. Int. J. Mol. Sci. 2020, 21, 6128.

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