Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold

BACKGROUND: Memory deficits in Alzheimer's disease (AD) manifest together with the loss of synapses caused by the disruption of the postsynaptic density (PSD), a network of scaffold proteins located in dendritic spines. However, the underlying molecular mechanisms remain elusive. Since it was shown that ProSAP2/Shank3 scaffold assembly within the PSD is Zn(2+)-dependent and that the amyloid beta protein (Aβ) is able to bind Zn(2+), we hypothesize that sequestration of Zn(2+ )ions by Aβ contributes to ProSAP/Shank platform malformation. RESULTS: To test this hypothesis, we designed multiple in vitro and in vivo assays demonstrating ProSAP/Shank dysregulation in rat hippocampal cultures following Aβ oligomer accumulation. These changes were independent from alterations on ProSAP/Shank transcriptional level. However, application of soluble Aβ prevented association of Zn(2+ )ions with ProSAP2/Shank3 in a cell-based assay and decreased the concentration of Zn(2+ )clusters within dendrites. Zn(2+ )supplementation or saturation of Aβ with Zn(2+ )ions prior to cell treatment was able to counter the effects induced by Aβ on synapse density and ProSAP2/Shank3 levels at the PSD. Interestingly, intracellular Zn(2+ )levels in APP-PS1 mice and human AD hippocampus are reduced along with a reduction in synapse density and synaptic ProSAP2/Shank3 and Shank1 protein levels. CONCLUSIONS: We conclude that sequestration of Zn(2+ )ions by Aβ significantly contributes to changes in ProSAP2/Shank3 platforms. These changes in turn lead to less consolidated (mature) synapses reflected by a decrease in Shank1 protein levels at the PSD and decreased synapse density in hippocampal neurons.