Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid β toxicity

Abstract

BackgroundAmyloid beta (Aβ) is the main agent responsible for the advent and progression of Alzheimer's disease. This peptide can at least partially antagonize nerve growth factor (NGF) signalling in neurons, which may be responsible for some of the effects produced by Aβ. Accordingly, better understanding the NGF signalling pathway may provide clues as to how to protect neurons from the toxic effects of Aβ.ResultsWe show here that Aβ activates the RhoA GTPase by binding to p75NTR, thereby preventing the NGF-induced activation of protein tyrosine phosphatase 1B (PTP1B) that is required for neuron survival. We also show that the inactivation of RhoA GTPase and the activation of PTP1B protect cultured hippocampal neurons against the noxious effects of Aβ. Indeed, either pharmacological inhibition of RhoA with C3 ADP ribosyl transferase or the transfection of cultured neurons with a dominant negative form of RhoA protects cultured hippocampal neurons from the effects of Aβ. In addition, over-expression of PTP1B also prevents the deleterious effects of Aβ on cultured hippocampal neurons.ConclusionOur findings indicate that potentiating the activity of NGF at the level of RhoA inactivation and PTP1B activation may represent a new means to combat the noxious effects of Aβ in Alzheimer's disease.

Cerebellin 4, a synaptic protein, enhances inhibitory activity and resistance of neurons to amyloid-β toxicity

“…We previously revealed that the Hes1 transcription factor mediates the effects of NGF on neuronal morphology and connectivity (SalamaCohen et al, 2005) and that the expression of Hes1 counteracted the neurotoxic effects of Aß (Arevalo et al, 2009;Chacon and RodriguezTebar, 2012;Chacon et al, 2011). To determine which genes are under either the direct or the indirect control of Hes1, a microarray assay was performed on 6 DIV cultured hippocampal neurons transduced with Sindbis virus overexpressing Hes1 and EGFP driven by different promoters (Fig.…”

“…Cultured neurons were transfected with different vectors using the Effectene Transfection Reagent (Qiagen GmbH, Hilden, Germany) according to the manufacturer's instructions. After an 18-hour incubation, the neurons were fixed and analyzed by ICC as described previously (Chacon and Rodriguez-Tebar, 2012;Chacon et al, 2011). The method to evaluate the dendritic morphology and to identify presynaptic terminals in dissociated cell cultures has also been published (Salama-Cohen et al, 2006).…”

“…Recombinant mouse b-NGF was obtained from R&D System (Minneapolis, MN, USA), whereas amyloid b (1e42) was obtained from NeoMPS (Strasbourg, France). Oligomeric forms of amyloid were obtained and characterized as described by Chacon et al (2011).…”

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…In vitro studies in cultured cells also reflect these changes. Aβ oligomers trigger a significant increase in RhoA activity in both SY5Y cells and in cultured hippocampal neurons [31][32][33][34]. Cdc42 and Rac1 levels have been reported to be elevated in select neuronal populations in AD brains compared with age-matched controls and have been proposed to perhaps play a role in activating cell cycle-related genes [35].…”

Amyloid beta1-42 peptide regulates microtubule stability independently of tau

“…Deregulation of Rho GTPase signaling has been implicated in neurotoxicity by Ab (Chacon et al, 2011;Petratos et al, 2008;Pozueta et al, 2013). Alterations in actin dynamics is generally considered the mechanism by which Rho contributes to the collapse of dendritic spines and impairs synaptic transmission, all early events occurring in neurons exposed to Ab (Lambert et al, 1998;Lefort et al, 2012;Lesné et al, 2006;Nimmrich and Ebert, 2009;Shankar et al, 2007).…”