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

Molecular Neurodegeneration

Tobias M Boeckers²  Craig C Garner³  Joseph D Buxbaum¹  Patrick R Hof⁵  Katrin I Andreasson⁴  Nathaniel S Woodling⁴  Michael Schoen²  Magali Arons³  Patrick T Udvardi²  Michael J Schmeisser²  Andreas M Grabrucker³ 

[1] Department of Genetics and Genomic Science, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA;Institute for Anatomy and Cell Biology, Ulm University, Albert Einstein Allee 11, Ulm, 89081, Germany;Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, 1201 Welch Road, Stanford, CA 94305-5485, USA;Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA94305 USA;Friedman Brain Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

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

Others  :  865606
DOI  :  10.1186/1750-1326-6-65

 received in 2011-05-13, accepted in 2011-09-22,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Grabrucker et al; licensee BioMed Central Ltd.

【 图 表 】

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