Why are hippocampal CA1 neurons vulnerable but motor cortex neurons resistant to transient ischemia?

J. Neurochem. (2012) 120, 574–585. It is well‐known that heat‐shock protein 70.1 (Hsp70.1), a major protein of the human Hsp70 family, plays cytoprotective roles by both its chaperone function and stabilization of lysosomal membranes. Recently, we found that calpain‐mediated cleavage of carbonylated Hsp70.1 in the hippocampal cornu Ammonis1 (CA1) contributes to neuronal death after transient global ischemia. This study aims to elucidate the differential neuronal vulnerability between the motor cortex and CA1 sector against ischemia/reperfusion. Fluoro‐Jade B staining and terminal deoxynucleotidyl transferase‐mediated dUTP‐nick‐end‐labeling analysis of the monkey brain undergoing 20 min whole brain ischemia followed by reperfusion, showed that the motor cortex is significantly resistant to the ischemic insult compared with CA1. Up‐regulation of Hsp70.1 but absence of its cleavage by calpain facilitated its binding with NF‐κB p65/IκBα complex to minimize NF‐κB p65 activation, which contributed to a neuroprotection in the motor cortex. In contrast, because activated μ‐calpain cleaved carbonylated Hsp70.1 in CA1, the resultant Hsp70.1 dysfunction not only destabilized lysosomal membrane but also induced a sustained activation of NF‐κB p65, both of which resulted in delayed neuronal death. We propose that the cascades underlying lysosomal stabilization and regulating NF‐κB activation by Hsp70.1 may influence neuronal survival/death after the ischemia/reperfusion. A differential role of Hsp70.1 between motor cortex and CA1 neurons after ischemia/reperfusion Recently, we found that calpain‐mediated cleavage of the carbonylated Hsp70.1 is crucial for the CA1 neuronal death after ischemia/reperfusion. We demonstrated here that Hsp70.1in motor cortex neurons lacking calpain activation can play a neuroprotection when compared with that in CA1, thus revealing a new mechanism underlying lysosomal stabilization and inhibiting NF‐κB p65 activation by Hsp70.1 may influence neuronal survival /death.