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

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Abstract
Akt signaling has been implicated in a number of diseases, but its role in brain disorders is less clear. Here, the authors report that CTMP, an endogenous inhibitor of Akt, is critical in the neurodegeneration that is associated with stroke. Blockade of CTMP in a stroke model rescues hippocampal neurons. Dysregulation of Akt signaling is important in a broad range of diseases that includes cancer, diabetes and heart disease. The role of Akt signaling in brain disorders is less clear. We found that global ischemia in intact rats triggered expression and activation of the Akt inhibitor CTMP (carboxyl-terminal modulator protein) in vulnerable hippocampal neurons and that CTMP bound and extinguished Akt activity and was essential to ischemia-induced neuronal death. Although ischemia induced a marked phosphorylation and nuclear translocation of Akt, phosphorylated Akt was not active in post-ischemic neurons, as assessed by kinase assays and phosphorylation of the downstream targets GSK-3β and FOXO3A. RNA interference–mediated depletion of CTMP in a clinically relevant model of stroke restored Akt activity and rescued hippocampal neurons. Our results indicate that CTMP is important in the neurodegeneration that is associated with stroke and identify CTMP as a therapeutic target for the amelioration of hippocampal injury and cognitive deficits.