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 europrotector.

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Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of b-amyloid (Aβ) in the brain, which produces progressive neuronal loss and dementia. We recently demonstrated that the noxious effects of AY#x03B2; on cultured hippocampal neurons are in part provoked by the antagonism of nerve growth factor (NGF) signalling, which impairs the activation of nuclear factor κB (NF-κB) by impeding the tyrosine phosphorylation of I-κBα. 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-κB through different approaches (overexpressing either the I-κB kinaseb, or p65/RelA/NF-κB). Alternatively neurons were exposed to TGFb1. Dendrite patterning, GABAergic connectivity and cell survival were analyzed by immunofluorescence microscopy. Hes1 expression was determined by real-time PCR. NF-κB activation was measured using the dual-luciferase reporter assay. Results: The expression of Hes1 abolished the effects of AY#x03B2; on dendritic patterning and GABAergic input, and it prevented the death of the cultured neurons. TGFb1, a known neuroprotector, could counteract the deleterious effects of AY#x03B2; by inducing NF-κB activation following the serine phosphorylation of I-κBα. Indeed, the number of GABAergic terminals generated by inducing Hes1 expression was doubled. Conclusion: Our data define some of the mechanisms involved in Aα-mediated cell death and they point to potential means to counteract this noxious activity.

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Early life stress Rearing HPA axis Monkey PET Social brain

DOI：

10.1186/alzrt134

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年份：

2012