CHACON FERNANDEZ, PEDRO JOSE, Garcia-Mejias, Rosa , Rodriguez-Tebar, Alfredo
No
Mol. Neurodegener.
Article
Científica
2.107
04/02/2011
000287300000001
Background: Amyloid beta (A beta) 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 A beta. Accordingly, better understanding the NGF signalling pathway may provide clues as to how to protect neurons from the toxic effects of A beta. Results: We show here that A beta activates the RhoA GTPase by binding to p75(NTR), 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 A beta. 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 A beta. In addition, over-expression of PTP1B also prevents the deleterious effects of A beta on cultured hippocampal neurons. Conclusion: 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 A beta in Alzheimer's disease.