title: Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold.
abstract: 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 Zn2+-dependent and that the amyloid beta protein (Aβ) is able to bind Zn2+, we hypothesize that sequestration of Zn2+ 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 Zn2+ ions with ProSAP2/Shank3 in a cell-based assay and decreased the concentration of Zn2+ clusters within dendrites. Zn2+ supplementation or saturation of Aβ with Zn2+ 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 Zn2+ 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 Zn2+ 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.
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Albert Einstein Allee 11, Ulm, 89081, Germany. tobias.boeckers@uni-ulm.de.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Grabrucker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schmeisser
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Udvardi
authors.forename: Magali
authors.initials: M
authors.lastname: Arons
authors.forename: Michael
authors.initials: M
authors.lastname: Schoen
authors.forename: Nathaniel S
authors.initials: NS
authors.lastname: Woodling
authors.forename: Katrin I
authors.initials: KI
authors.lastname: Andreasson
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Craig C
authors.initials: CC
authors.lastname: Garner
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers