Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts
Authors
Guarnieri, Giulia
Sarchielli, Erica
Comeglio, Paolo
Herrera-Puerta, Erika
Piaceri, Irene
Benelli, Matteo
Maggi, Mario
Gallina, Pasquale
Vannelli, Gabriella Barbara
Morelli, Annamaria
Publication Date
2020-08-25Journal Title
International Journal of Molecular Sciences
Publisher
MDPI
Volume
21
Issue
17
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Guarnieri, G., Sarchielli, E., Comeglio, P., Herrera-Puerta, E., Piaceri, I., Nacmias, B., Benelli, M., et al. (2020). Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts. International Journal of Molecular Sciences, 21 (17)https://doi.org/10.3390/ijms21176128
Abstract
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.
Keywords
neuroinflammation, Alzheimer’s disease, neurogenesis, human fetal neurons, DNA methylation, nucleus basalis of Meynert, ciliogenesis, NGF, TNFα receptors
Identifiers
External DOI: https://doi.org/10.3390/ijms21176128
This record's URL: https://www.repository.cam.ac.uk/handle/1810/309666
Rights
Licence:
https://creativecommons.org/licenses/by/4.0/