Search

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.

Objective: The efficacy and safety of atomoxetine, the only licensed non-stimulant pharmacological treatment option for ADHD in Europe, is well investigated in clinical trials, the long-term effects in the developing brain still remain elusive. In vitro studies prove that besides the well-known inhibition of the norepinephrine transporter (NET) atomoxetine acts as a blocker of the N-methyl-D-aspartate (NMDA) receptor. Here we present an in vivo study carried out to investigate atomoxetine’s effect in the maturing rat brain. Methods: Pregnant Crl:SD(CD) rats were treated with atomoxetine (3 mg/kg, i.p.) and sodium chloride (0.9%, i.p.), for the period equivalent to human second to third trimenon of pregnancy. After the end of treatment hippocampus, prefrontal cortex, mesencephalon and striatum from embryos and dams were isolated for analysis of gene expression. Results: Quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed altered expression of genes of the monoaminergic and glutamatergic system in both embryos and dams. Discussion: This study gives hints that atomoxetine might alter transcriptional regulation of genes of the monoaminergic and glutamatergic system in an age-dependent manner. Conclusion: Atomoxetine alters gene expression in vivo. [ABSTRACT FROM AUTHOR]