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


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.

9 Reads
  • Source
    • " ( Jacobsen et al . , 2006 ; Rocher et al . , 2008 ; D ' Amelio et al . , 2011 ; Perez - Cruz et al . , 2011 ; Ricobaraza et al . , 2012 ) . The molecular mechanisms leading to synapse dysfunction and loss in AD are largely unclear . Aβ oligomers impair glutamatergic neurotransmission in an activity - dependent manner ( Lacor et al . , 2004 ; Deshpande et al . , 2009 ) and cause synapse loss by postsynaptic mechanisms involving deregulation , removal and / or mistargeting of extrasynaptic NMDA and synaptic α - amino - 3 - hydroxy - 5 - methylisoxazole - 4 - propionic acid ( AMPA ) glutamate receptors ( Shankar et al . , 2007 ; D ' Amelio et al . , 2011 ; Miñano - Molina et al . , 2011 ) . For i"
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal accumulation of β-amyloid and tau and synapse dysfunction in memory-related neural circuits. Pathological and functional changes in the medial temporal lobe, a region essential for explicit memory encoding, contribute to cognitive decline in AD. Surprisingly, functional imaging studies show increased activity of the hippocampus and associated cortical regions during memory tasks in presymptomatic and early AD stages, whereas brain activity declines as the disease progresses. These findings suggest an emerging scenario where early pathogenic events might increase neuronal excitability leading to enhanced brain activity before clinical manifestations of the disease, a stage that is followed by decreased brain activity as neurodegeneration progresses. The mechanisms linking pathology with synaptic excitability and plasticity changes leading to memory loss in AD remain largely unclear. Recent studies suggest that increased brain activity parallels enhanced expression of genes involved in synaptic transmission and plasticity in preclinical stages, whereas expression of synaptic and activity-dependent genes are reduced by the onset of pathological and cognitive symptoms. Here, we review recent evidences indicating a relationship between transcriptional deregulation of synaptic genes and neuronal activity and memory loss in AD and mouse models. These findings provide the basis for potential clinical applications of memory-related transcriptional programs and their regulatory mechanisms as novel biomarkers and therapeutic targets to restore brain function in AD and other cognitive disorders.
    Frontiers in Cellular Neuroscience 08/2015; 9. DOI:10.3389/fncel.2015.00318 · 4.29 Impact Factor
  • Source
    • "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"
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In early Alzheimer's disease (AD) brain, reduction of sigma-1 receptors (σ1R) is detected. In this study, we employed male heterozygous σ1R knockout (σ1R+/-) mice showing normal cognitive performance to investigate association of σ1R deficiency with AD risk. Herein we report that a single injection (i.c.v.) of Aβ25-35 impaired spatial memory with approximately 25% death of pyramidal cells in the hippocampal CA1 region of WT mice (Aβ25-35-WT mice), whereas it did not cause such impairments in σ1R+/- mice (Aβ25-35-σ1R+/- mice). Compared with WT mice, Aβ25-35-WT mice showed increased levels of NMDA-activated currents (INMDA) and NR2B phosphorylation (phospho-NR2B) in the hippocampal CA1 region at 48 h after Aβ25-35-injection (post-Aβ25-35) followed by approximately 40% decline at 72 h post-Aβ25-35 of their respective control levels, which was inhibited by the σ1R antagonist NE100. In Aβ25-35-WT mice, the administration of NR2B inhibitor Ro25-6981 or NE100 on day 1-4 post-Aβ25-35 attenuated the memory deficits and loss of pyramidal cells. By contrast, Aβ25-35-σ1R+/- mice showed a slight increase in the INMDA density and the phospho-NR2B at 48 h or 72 h post-Aβ25-35 compared to σ1R+/- mice. Treatment with σ1R agonist PRE084 in Aβ25-35-σ1R+/- mice caused the same changes in the INMDA density and the phospho-NR2B as those in Aβ25-35-WT mice. Furthermore, Aβ25-35-σ1R+/- mice treated with the NMDA receptor agonist NMDA or PRE084 on day 1-4 post-Aβ25-35 showed a loss of neuronal cells and memory impairment. These results indicate that the σ1R deficiency can reduce Aβ25-35-induced neuronal cell death and cognitive deficits through suppressing Aβ25-35-enhanced NR2B phosphorylation.
    Neuropharmacology 10/2014; 89. DOI:10.1016/j.neuropharm.2014.09.027 · 5.11 Impact Factor
Show more