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Open Access Research article

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

Andreas M Grabrucker12, Michael J Schmeisser1, Patrick T Udvardi1, Magali Arons2, Michael Schoen1, Nathaniel S Woodling3, Katrin I Andreasson3, Patrick R Hof45, Joseph D Buxbaum4567, Craig C Garner2 and Tobias M Boeckers1*

Author Affiliations

1 Institute for Anatomy and Cell Biology, Ulm University, Albert Einstein Allee 11, Ulm, 89081, Germany

2 Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, 1201 Welch Road, Stanford, CA 94305-5485, USA

3 Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305 USA

4 Fishberg Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

5 Friedman Brain Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

6 Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

7 Department of Genetics and Genomic Science, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

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Molecular Neurodegeneration 2011, 6:65  doi:10.1186/1750-1326-6-65

Published: 22 September 2011

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.

Keywords:
PSD; Alzheimer's disease; ProSAP2; Shank3; Shank1; Amyloid; Oligomers; Zn2+; Hippocampus; synapse