The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death

Abstract

Dysregulation of Akt signaling is a critical player in a broad range of diseases including cancer, diabetes and heart disease. The role of Akt signaling in brain disorders is less clear. Here we show that global ischemia in intact rats triggers expression and activation of the Akt inhibitor CTMP (Carboxyl-Terminal Modulator Protein) in vulnerable hippocampal neurons, that CTMP binds and extinguishes Akt activity and that CTMP is essential to ischemia-induced neuronal death. Whereas ischemia induces a dramatic phosphorylation and nuclear translocation of Akt, p-Akt in postischemic neurons is not active, as assessed by kinase assays and phosphorylation of downstream targets GSK-3β and FOXO3A. RNA-interference-mediated depletion of CTMP in a clinically relevant model of stroke restores Akt activity and rescues hippocampal neurons. These findings document a critical role for CTMP in the neurodegeneration associated with stroke and identify CTMP as a novel therapeutic target for amelioration of hippocampal injury and cognitive deficits.