A Role for Synaptic Zinc in Activity-Dependent A Oligomer Formation and Accumulation at Excitatory Synapses

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2009; 29(13):4004-15. DOI: 10.1523/JNEUROSCI.5980-08.2009
Source: PubMed

ABSTRACT Soluble amyloid beta oligomers (AbetaOs) interfere with synaptic function and bind with high affinity to synapses, but the mechanism underlying AbetaO synaptic targeting is not known. Here, we show that the accumulation of synthetic or native Alzheimer's disease (AD)-brain oligomers at synapses is regulated by synaptic activity. Electrical or chemical stimulation increased AbetaO synaptic localization and enhanced oligomer formation at synaptic terminals, whereas inhibition with TTX blocked AbetaO synaptic localization and reduced AbetaO synaptic load. The zinc-binding 8-OH-quinoline clioquinol markedly reduced AbetaO synaptic targeting, which was also reduced in brain sections of animals deficient in the synaptic vesicle zinc transporter ZnT3, indicating that vesicular zinc released during neurotransmission is critical for AbetaO synaptic targeting. Oligomers were not internalized in recycled vesicles but remained at the cell surface, where they colocalized with NR2B NMDA receptor subunits. Furthermore, NMDA antagonists blocked AbetaO synaptic targeting, implicating excitatory receptor activity in oligomer formation and accumulation at synapses. In AD brains, oligomers of different size colocalized with synaptic markers in hippocampus and cortex, where oligomer synaptic accumulation correlated with synaptic loss.

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    • "Research during the last decade has identified the accumulation of soluble synaptotoxic amyloid oligomers ( AßO ) as the likely reason for the early - onset impairment of synaptic plasticity in many AD mouse models . AßOs have been shown to bind to syn - apses in an activity - and NMDAR - dependent manner ( Deshpande et al . , 2009 ) where they compromise synaptic function via multi - ple mechanisms ( e . g . , Benilova et al . , 2012 ; Brouillette et al . , 2012 ; Deshpande et al . , 2006 ; Haass and Selkoe , 2007 ; Lacor et al . , 2007 ) . However , inconsistent with the amyloid cascade hypothesis of AD ( Hardy and Selkoe , 2002 ) , it is tau pathology and not A"
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    ABSTRACT: Cognitive decline, the hallmark of Alzheimer's disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the "diagnosis" of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer's disease progression. Here, we demonstrate that impaired late LTD (>3 hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3β) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3β at Y216 and reduced total phosphatase activity in biochemical assays of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3β appeared to downregulate GSK3ß activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY-Tau22 mice.
    Neurobiology of Aging 02/2015; DOI:10.1016/j.neurobiolaging.2014.09.015. · 5.01 Impact Factor
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    • "Using the s 1 R knockout mice showing normal spatial cognition, the present study provides, for the first time, in vivo evidence that the s 1 R deficiency can reduce Ab 25e35 -induce hippocampal neuronal cell death and spatial cognitive deficits through suppressing Ab 25e35 -increased NR2B phosphorylation. Colocalization of Ab and NR2B subunit is observed in hippocampal neurons (Deshpande et al., 2009). Soluble Ab oligomers had been demonstrated to enhance the activation of NR2B-containing NMDAr (Li et al., 2011). "
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    Neuropharmacology 10/2014; 89. DOI:10.1016/j.neuropharm.2014.09.027 · 5.11 Impact Factor
    • "Conversely, Ab-induced activation of GluN2A-containing NMDARs in non-neuronal cells, namely in Xenopus laevis oocytes (Texidó et al., 2011) and HEK293cells (Domingues et al., 2007), was previously reported. In the AD brain and human cortical neurons, excitatory synapses containing the GluN2B subunit of the NMDARs appear to be the main sites of oligomer accumulation (Deshpande et al., 2009). Recently, we showed that Ab increased Ca 2þ i levels through the activation of NMDARs containing GluN2B subunits, shown to be present at the membrane surface in cortical neurons (Ferreira et al., 2012), which may result in microtubule disassembly and reduced neurite length (Mota et al., 2012). "
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    Neurobiology of Aging 09/2014; 36(2). DOI:10.1016/j.neurobiolaging.2014.09.006 · 5.01 Impact Factor
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