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

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta-amyloid (A beta) in the brain, which produces progressive neuronal loss and dementia. We recently demonstrated that the noxious effects of A beta on cultured hippocampal neurons are in part provoked by the antagonism of nerve growth factor (NGF) signalling, which impairs the activation of nuclear factor kappa B (NF-kappa B) by impeding the tyrosine phosphorylation of I-kappa B alpha. 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-kappa B through different approaches (overexpressing either the I-kappa B kinaseb, or p65/RelA/NF-kappa B). Alternatively neurons were exposed to TGF beta 1. Dendrite patterning, GABAergic connectivity and cell survival were analyzed by immunofluorescence microscopy. Hes1 expression was determined by real-time PCR. NF-kappa B activation was measured using the dual-luciferase reporter assay. Results: The expression of Hes1 abolished the effects of Ab on dendritic patterning and GABAergic input, and it prevented the death of the cultured neurons. TGF beta 1, a known neuroprotector, could counteract the deleterious effects of Ab by inducing NF-kappa B activation following the serine phosphorylation of I-kappa B alpha. Indeed, the number of GABAergic terminals generated by inducing Hes1 expression was doubled. Conclusion: Our data define some of the mechanisms involved in A beta-mediated cell death and they point to potential means to counteract this noxious activity.