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

DOI: 10.1186/1750-1326-6-14

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We 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.Our 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.According to the amyloid hypothesis, amyloid beta (Aβ) aggregates form deposits in the brain, the process that precipitates the different manifestations of Alzheimer's disease (AD) [1]. Consequently, most therapeutic approaches to treat AD centre on this peptide: on the one hand attempting to limit the production of Aβ or the formation of fibrils and aggregates [2,3], while on the other hand, favouring its clearance. Therapeutic approaches aimed at clearing Aβ plaques have received special attention, and methods for active or passive immunisation have proven effective in reducing Aβ content in the brain. Nevertheless, these strategies have failed to conclusively ameliorate or retard cognitive deterioration in AD patients [4,5].Another approach that could be considered involves blocking the signals induced by Aβ that provoke neuronal death. However, despite extensive studies into the effects of Aβ on neurons, our understanding of Aβ signalling remains fragmented, and a consistent framework for such processes has yet to be defined. Still, recent publications have reinforced the notion that Aβ interferes


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