Picomolar beta-amyloid modulates hippocampal synaptic plasticity via inhibitor of apoptosis protein regulation of caspase-3 activity and RhoGDP dissociation inhibitor

Picomolar beta-amyloid modulates hippocampal synaptic plasticity via inhibitor of apoptosis protein regulation of caspase-3 activity and RhoGDP dissociation inhibitor. Pero M.E., Ribe E.M., Jean Y.Y., Troy C.M. Picomolar beta-amyloid (Abeta) positively modulates hippocampal synaptic plasticity and memory, whereas nanomolar and higher concentrations lead to inhibition of long-term potentiation, loss of spines and eventually neuronal death. We have previously shown that the toxic effects of Abeta are mediated by activation of caspase-2, despite concurrent activation of caspase-3 (caspase-3 is neither necessary nor sufficient for toxicity). In the current work we examine the function of caspase-3 in the effects of pM Abeta. Treatment of primary hippocampal neurons with pM Abeta leads to a rapid increase in spine density that is accompanied by a rapid increase in caspase-3 activity in purified synaptosomes. Effects are seen within 30 minutes of treatment of the cultures. As this effect is rapid, we posited that the synapses contain cleaved (activated) caspase-3 that is inhibited by endogenous inhibitor of apoptosis proteins, IAPs. We found that the synaptosomal fraction contains cIAP1 and XIAP, and co-immunoprecipitation shows that there are complexes of cIAP1-cleaved caspase-3 and XIAP-cleaved caspase-3. Treatment of cultures with pM Abeta induces a decrease in the cIAP1-cleaved caspase-3 interaction, but no change in the XIAP-cleaved caspase-3 interaction, suggesting that the increase in caspase-3 activity is modulated by cIAP1. Actin, the major component of spines, is a substrate of caspase-3, and we find that pM Abeta leads to an increase in cleaved actin. siRNA knockdown of caspase-3 prevents the effects of pM Abeta and siRNA knockdown of cIAP1 potentiates the effects of pM Abeta on spine density. Surprisingly we found that siRNA knockdown of XIAP prevented the effects of pM Abeta. A recent study has shown that XIAP can bind to RhoGDI (Rho GDP dissociation inhibitor), leading to an increase in f-actin. Co-IP shows that pM Abeta increases the XIAP-RhoGDI interaction. Our data show that spine dynamics can be regulated by pM Abeta through both induction of caspase-3 activity and sequestration of RhoGDI by XIAP.