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Increased expression of the homologue of enhancer-of-split 1 protects neurons from beta amyloid neurotoxicity and hints at an alternative role for transforming growth factor beta1 as a neuroprotector

AutorChacón, Pedro J. ; Rodríguez-Tebar, Alfredo
Fecha de publicación2012
EditorBioMed Central
CitaciónAlzheimer's Research and Therapy 4(4): 31 (2012)
Resumen[Introduction]: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of -amyloid (A) in the brain, which produces progressive neuronal loss and dementia. We recently demonstrated that the noxious effects of A on cultured hippocampal neurons are in part provoked by the antagonism of nerve growth factor (NGF) signalling, which impairs the activation of nuclear factor B (NF-B) by impeding the tyrosine phosphorylation of I-B. As a result, the expression of the homologue of Enhancer-of split 1 (Hes1) gene is downregulated and ultimately, gamma-aminobutyric acid (GABA)-ergic connectivity is lost. [Methods]: Hes1 activity was promoted in cultured hippocampal neurons by overexpressing a Hes1-encoding plasmid or by upregulating this gene by activating NF-B through different approaches (overexpressing either the I-B kinase, or p65/RelA/NF-B). Alternatively neurons were exposed to TGF1. Dendrite patterning, GABAergic connectivity and cell survival were analyzed by immunofluorescence microscopy. Hes1 expression was determined by real-time PCR. NF-B activation was measured using the dual-luciferase reporter assay. [Results]: The expression of Hes1 abolished the effects of A on dendritic patterning and GABAergic input, and it prevented the death of the cultured neurons. TGF1, a known neuroprotector, could counteract the deleterious effects of A by inducing NF-B activation following the serine phosphorylation of I-B. Indeed, the number of GABAergic terminals generated by inducing Hes1 expression was doubled. [Conclusion]: Our data define some of the mechanisms involved in A-mediated cell death and they point to potential means to counteract this noxious activity.
Versión del editorhttp://dx.doi.org/10.1186/alzrt134
URIhttp://hdl.handle.net/10261/121673
DOI10.1186/alzrt134
Identificadoresissn: 1758-9193
e-issn: 1758-9193
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