c-Abl Tyrosine Kinase-Mediated Neuronal Apoptosis in Subarachnoid Hemorrhage by Modulating the LRP-1-Dependent Akt/GSK3 β Survival Pathway

AbstractAccumulating evidence suggests that neuronal apoptosis plays a critical role in early brain injury (EBI) after subarachnoid hemorrhage (SAH), and the inhibition of apoptosis can induce neuroprotective effects in SAH animal models. c-Abl has been reported to promote neuronal apoptosis in Alzheimer ’s disease and cerebral ischemia, but its role in SAH had not been illuminated until now. In the present study, the effect of c-Abl on neuronal apoptosis induced by SAH was investigated. c-Abl protein levels and neuronal apoptosis were markedly increased 24 h after SAH, and the inhibition of endo genous c-Abl reduced neuronal apoptosis and mortality and ameliorated neurological deficits. Furthermore, c-Abl inhibition decreased the expression of cleaved caspase-3 (CC-3) after SAH. These results demonstrate the proapoptotic effect of c-Abl in EBI after SAH. Additionally, c-Abl inhibition furth er enhanced the SAH-induced phosphorylation of Akt and glycogen synthase kinase (GSK)3β. LY294002 abrogated the beneficial effects of targeting c-Abl and exacerbated neuronal apoptosis after SAH. SAH decreased LRP-1 levels and downregulated LRP-1 by RAP, and LRP-1 small interfering RNA (siRNA) indu ced a dramatic decrease in Akt/GSK3β activation in the presence of c-Abl siRNA. This is the first report showing that the c-Abl tyrosine kinase may play a key role in SAH-induced neuronal apoptosis by regulating the LRP-1-dependent Akt/GSK3β survival pathway. Thus, c-Abl has the potential...
Source: Journal of Molecular Neuroscience - Category: Neuroscience Source Type: research