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Cited by 232Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

Open access
Deshpande, Atul, Kawai, Hideki, Metherate, Raju, Glabe, Charles G., Busciglio, Jorge·2009·The Journal of Neuroscience
DOI 10.1523/jneurosci.5980-08.2009PMC PMC6665357
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Abstract

Soluble amyloid β oligomers (AβOs) interfere with synaptic function and bind with high affinity to synapses, but the mechanism underlying AβO 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 AβO synaptic localization and enhanced oligomer formation at synaptic terminals, whereas inhibition with TTX blocked AβO synaptic localization and reduced AβO synaptic load. The zinc-binding 8-OH-quinoline clioquinol markedly reduced AβO 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 AβO 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 AβO 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.

AI snapshot

Written from the paper’s full text.

TL;DR

This study shows that synaptic activity promotes Aβ oligomer formation and accumulation at excitatory synapses, with vesicular zinc and NMDA receptor activity required for this targeting. Synthetic and AD-brain-derived oligomers localize to synapses in an activity-dependent manner, and high oligomer synaptic localization is associated with synaptic loss in AD brains.

Key findings

  • In rat hippocampal slices, 500 nM AβO synaptic localization was 14.09 ± 4.17% under basal conditions but increased to 63.74 ± 7.50% with 20 mM KCl and 57.81 ± 10.84% with 100 µM glutamate; TTX blocked the glutamate-induced increase to 8.96 ± 3.40%.
  • The zinc-binding compound clioquinol reduced stimulated AβO synaptic localization (KCl: 63.4 ± 6.62% to 26.46 ± 8.64%; glutamate: 62.4 ± 6.07% to 22.27 ± 5.05%), and ZnT3−/− slices showed dramatically reduced AβO synaptic localization after KCl or glutamate.
  • NMDA receptor antagonists reduced AβO synaptic targeting (APV: 65.81 ± 15.36% to 22.12 ± 14.30%; memantine: to 20.82 ± 9.76%; ifenprodil: to 37.76 ± 8.91%), whereas CNQX did not; glutamate increased oligomer colocalization with NR2B from 19.89 ± 4.82% to 47.11 ± 10.72%.
  • In human tissue, oligomer immunoreactivity was detected in 8 of 15 AD cases and 2 of 10 controls; oligomer density varied from 2.49 ± 1.11% to 12.32 ± 2.63%, and reduced synaptic density was consistently observed in cases with high oligomer synaptic localization.

Methods

  • Acute hippocampal slices from adult Sprague Dawley rats and WT or ZnT3−/− mice, human cortical neuron cultures from 16- to 21-week fetal brain tissue, and human brain sections from 15 AD and 10 nondemented cases were used.
  • Slices/cultures were treated with synthetic AβOs or ADDLs (mostly 500 nM), monomeric Aβ (5 µM), KCl (20 mM), glutamate (100 µM), TTX (1–2 µM), clioquinol (1 µM), APV/memantine (10 µM), ifenprodil (5 µM), or CNQX (10 µM), with chemical or electrical stimulation and AM4-64 endocytosis tracking.
  • Main analyses were immunofluorescence colocalization with synaptophysin, PSD-95, NR2B, and conformation-specific oligomer antibodies, image analysis, native/denaturing PAGE/Western blot, and t tests or ANOVA with p < 0.05.

Limitations

  • Stated: the authors note that variation among AD cases could reflect differences in neuronal activity or postmortem interval, and that additional studies are required to link zinc functional alterations to cognitive deficits and to determine whether different oligomer assemblies differ in synaptic binding or dysfunction.
  • Evident: the human tissue findings are correlational and based on small numbers (15 AD, 10 controls; only 8 AD and 2 controls oligomer-positive), so the association between oligomer synaptic localization and synaptic loss cannot establish causation.
  • Evident: mechanistic conclusions rely largely on acute rodent slices and cultured human neurons with exogenous oligomers, mostly at 500 nM, so in vivo endogenous oligomer concentrations and chronic disease dynamics are not directly tested.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1523/jneurosci.5980-08.2009

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 27 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    There is a correlation between oligomer synaptic accumulation and synaptic loss in AD brains.

    “where we observed a correlation between oligomer synaptic accumulation and synaptic loss.”
    Quote in the paperSubstantial claim
  • Findingown data

    NMDA antagonists blocked AβO synaptic targeting.

    “Furthermore, NMDA antagonists blocked A␤O synaptic targeting”
    Quote in the paperSubstantial claim
  • Findingown data

    TTX blocked AβO synaptic localization.

    “inhibition with TTX blocked A␤O synaptic localization”
    • Also stated in: § Synaptic activity modulates A␤O targeting to synaptic terminals · plain
      “Preincubation of slices with 2 M TTX for 20 min before the addition of A␤O and glutamate completely blocked the increase in A␤O synaptic localization (8.96 Ϯ 3.40%)”
    Quote in the paperSubstantial claim
  • Findingown data

    Oligomer synaptic targeting was prevented by NMDA receptor antagonists.

    “and by NMDA receptor antagonists”
    Quote in the paperSubstantial claim
  • Findingown data

    Electrical or chemical stimulation enhanced oligomer formation at synaptic terminals.

    “Electrical or chemical stimulation increased A␤O synaptic localization and enhanced oligomer formation at synaptic terminals”
    • Also stated in: § Synaptic targeting of A␤O is mediated by zinc · hedged
      “suggesting that synaptic activity enhanced oligomer formation from monomeric A␤.”
    Quote in the paperSubstantial claim
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Synaptic activity dramatically enhances both oligomer formation and localization at synaptic sites in rat and mouse hippocampal slices and primary HCNs in culture.

    “Here, we show that synaptic activity dramatically enhances both oligomer formation and localization at synaptic sites in rat and mouse hippocampal slices and primary HCNs in culture.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Oligomers were not internalized in recycled vesicles but remained at the cell surface.

    “Oligomers were not internalized in recycled vesicles but remained at the cell surface”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Comparable results were obtained using ADDL preparations.

    “Comparable results were obtained using ADDL preparations (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Stimulation with KCl or glutamate resulted in a marked elevation in AβO synaptic localization in WT mouse slices, which was suppressed by coincubation with TTX.

    “Stimulation with KCl or glutamate resulted in a marked elevation in A␤O synaptic localization, which was suppressed by coincubation with TTX (Fig. 2 B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The increase in oligomer synaptic accumulation was completely prevented by coincubation with A11 but not by coincubation with nonimmune Ig.

    “The increase in oligomer synaptic accumulation was completely prevented by coincubation with A11 but not by coincubation with nonimmune Ig (Fig. 1 E)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingreasoning

    AβO synaptic localization under unstimulated conditions was higher in HCNs than in hippocampal slices.

    “with the exception that A␤O synaptic localization under unstimulated conditions was higher in HCNs than in hippocampal slices”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At short incubation times, we did not detect AβO internalization in recycled vesicles but a sustained presence of AβO at synaptic surface, which peaked between 30 min to 1 h.

    “However, at short incubation times, we did not detect A␤O internalization in recycled vesicles but a sustained presence of A␤O at the synaptic surface, which peaked between 30 min to 1 h.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Similar results were obtained using ADDL preparations.

    “Similar results were obtained using ADDL preparations (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither A11 nor NU-2 exhibited significant immunoreactivity associated with neuritic plaques or tangles.

    “Neither A11 nor NU-2 exhibited significant immunoreactivity associated with neuritic plaques or tangles (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The increase in oligomer synaptic localization after electrical stimulation was prevented by addition of oligomers and antibody A11 to slices, but not by addition of oligomers and nonimmune Ig.

    “This increase was prevented by the addition of oligomers and antibody A11 to the slices, but not by the addition of oligomers and a nonimmune Ig (NI-Ab).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    KCl or glutamate significantly increased oligomer synaptic localization.

    “KCl or glutamate significantly increased oligomer synaptic localization.”
    • Also stated in: § Discussion · boosted
      “Stimulation of neuronal activity by KCl or glutamate resulted in dramatic increases in A␤O synaptic localization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stimulation with KCl significantly increased both the frequency and synaptic localization of anti-annular protofibril immunofluorescence on rat slices.

    “but stimulation with KCl significantly increased both the frequency and synaptic localization of the immunofluorescence (Fig. 3B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The addition of KCl resulted in a time-dependent increase in appearance of A11-positive puncta, which colocalized with synaptophysin.

    “The addition of KCl resulted in a time-dependent increase in the appearance of A11-positive puncta, which colocalized with synaptophysin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was significant variation in extent of oligomer deposition among positive cases, as well as regional variations in individual cases.

    “There was significant variation in the extent of oligomer deposition among positive cases, as well as regional variations in individual cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    NU-2 detected smaller puncta, whereas A11 detected mainly medium-sized puncta and anti-annular protofibrils detected larger puncta.

    “NU-2 detected smaller puncta, whereas A11 detected mainly medium-sized puncta and antiannular protofibrils detected larger puncta.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Under denaturing conditions, 6F/3D recognized two major low molecular weight bands.

    “Under denaturing conditions, A11 staining was negative, and 6F/3D recognized two major low molecular weight bands.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Treatment with TTX blocked synaptic activity, vesicle recycling, and the incorporation of AM4-64 into vesicles.

    “Treatment with TTX blocked synaptic activity, vesicle recycling, and the incorporation of AM4-64 into vesicles.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AD case 24-01 exhibited lower oligomeric signal but high synaptic localization.

    “whereas case 24-01 exhibited lower oligomeric signal but high synaptic localization.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Soluble oligomers perturb synaptic function by inhibiting long-term potentiation.

    “Soluble oligomers perturb synaptic function by inhibiting long-term potentiation (Lambert et al., 1998;Walsh et al., 2002;Wang et al., 2002;Cleary et al., 2005;Townsend et al., 2006)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Lambert et al., 1998

      Not checked in the free run.

    • cites Walsh et al., 2002

      Not checked in the free run.

    • cites Townsend et al., 2006

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Aβ is a metal-binding protein with high affinity for copper and zinc.

    “A␤ is a metal-binding protein with high affinity for copper and zinc (Bush et al., 1994a;Atwood et al., 2000).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bush et al., 1994a

      Not checked in the free run.

    • cites Atwood et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Zinc and excitatory neurotransmission play a role in the synaptic accumulation of AβO.

    “suggesting a role for zinc and excitatory neurotransmission in the synaptic accumulation of A␤O.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some intermediate Aβ species bind to conformation-specific antibodies such as the polyclonal antibody A11.

    “Some of these intermediate A␤ species, collectively designated as soluble A␤ oligomers (A␤Os) (Glabe, 2004), bind to conformation-specific antibodies such as the polyclonal antibody A11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kayed et al., 2003

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Competition with an antigenic peptide, use of a nonimmune IgG instead of a primary antibody, or omission of a primary antibody resulted in complete elimination of specific fluorescent signals.

    “Competition with an antigenic peptide, use of a nonimmune IgG instead of a primary antibody, or omission of a primary antibody resulted in complete elimination of specific fluorescent signals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Knocking out the ZnT3 gene results in complete disappearance of zinc in synaptic vesicles throughout the brain without affecting other nonvesicular pools of zinc.

    “Knocking out the ZnT3 gene results in complete disappearance of zinc in synaptic vesicles throughout the brain without affecting other nonvesicular pools of zinc (Cole et al., 1999).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cole et al., 1999

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Each individual experiment was performed in triplicate.

    “Each individual experiment was performed in triplicate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All individual experiments were repeated at least three times in acute slices or dissociated cultures derived from different brain specimens.

    “All individual experiments were repeated at least three times in acute slices or dissociated cultures derived from different brain specimens.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Both AβOs and ADDLs bind rapidly and with remarkable specificity to synapses in HCN cultures.

    “Both A␤Os and ADDLs bind rapidly and with remarkable specificity to synapses in HCN cultures (Deshpande et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Deshpande et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Zinc is released during synaptic activity, reaching extracellular concentrations close to 300 μM.

    “Zinc is released during synaptic activity, reaching extracellular concentrations close to 300 M (Frederickson and Bush, 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Frederickson and Bush, 2001

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The identity of cultures or human brain sections was coded to avoid experimental bias.

    “The identity of the cultures or human brain sections was coded to avoid experimental bias.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Clioquinol decreases Aβ deposits and improves cognitive deficits in AD animal models.

    “which has been shown to decrease A␤ deposits and improve cognitive deficits in AD animal models (Cherny et al., 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cherny et al., 2001

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A conformation-dependent antibody specifically recognizes annular protofibrils but not mature amyloid fibrils or spherical oligomers.

    “We also analyzed oligomer formation using a conformation-dependent antibody that specifically recognizes annular protofibrils but not mature amyloid fibrils or spherical oligomers (Kayed and Glabe, 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kayed and Glabe, 2006

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A11 recognizes a generic backbone epitope common to the oligomeric state independently of the primary protein sequence.

    “which recognizes a generic backbone epitope common to the oligomeric state independently of the primary protein sequence (Kayed et al., 2003)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kayed et al., 2003

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Study design and conductreasoning

    TetraSpeck beads were used as a positive control to correct for potential plane shifts.

    “To confirm the colocalization of fluorescent signals, TetraSpeck beads (TetraSpeck Fluorescent Microspheres Sampler kit; Invitrogen) were used as a positive control.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Clioquinol does not interact directly with Aβ but binds selectively to the Aβ-metal ion complex and dissociates the metal ion from Aβ.

    “Clioquinol does not interact directly with A␤ but binds selectively to the A␤metal ion complex and dissociates the metal ion from A␤ (Cherny et al., 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cherny et al., 2001

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Zinc sequestration in Aβ-zinc complexes may lead to reduced zinc availability at synaptic terminals and consequent loss of zinc modulatory activity at excitatory synapses.

    “Alternatively, zinc sequestration in A␤-zinc complexes may lead to reduced zinc availability at synaptic terminals and the consequent loss of zinc modulatory activity at excitatory synapses (Frederickson et al., 2005).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Aberrant neuronal activity may stimulate oligomer accumulation at synapses during disease process, eventually leading to impaired synaptic plasticity and synaptic loss.

    “aberrant neuronal activity may stimulate oligomer accumulation at synapses during the disease process, eventually leading to impaired synaptic plasticity and synaptic loss.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A11-negative soluble fractions from age-matched brains with no AD pathology were used as controls.

    “A11-negative soluble fractions from age-matched brains with no AD pathology were used as controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Neuronal activity not only enhanced oligomer targeting but also facilitated oligomer formation at synaptic sites.

    “neuronal activity not only enhanced oligomer targeting but also facilitated oligomer formation at synaptic sites (Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Native oligomers extracted from AD brains can actively bind to synaptic terminals and this binding is modulated by neuronal activity.

    “Thus, native oligomers extracted from AD brains can actively bind to synaptic terminals and this binding is modulated by neuronal activity.”
    Quote in the paperSubstantial claim
39 of 39

  • The paper relies on this without support.

    The mechanism underlying AβO synaptic targeting is not known.

    “but the mechanism underlying A␤O synaptic targeting is not known.”

  • The paper relies on this without support.

    Zinc is concentrated in synaptic vesicles at glutamatergic synapses throughout the cortex and the hippocampal formation.

    “Zinc promotes A␤ oligomerization (Curtain et al., 2001) and is concentrated in synaptic vesicles at glutamatergic synapses throughout the cortex and the hippocampal formation.”

  • The paper relies on this without support.

    ZnT3 is responsible for the shuttling of zinc into synaptic vesicles.

    “ZnT3 is responsible for the shuttling of zinc into synaptic vesicles.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • TTX concentration differs between Methods and Results

    Major

    The chemical-modulation method specifies 1 M TTX, whereas the corresponding hippocampal-slice result reports preincubation with 2 M TTX.

  • Conflicting reports of A11-positive structures at five minutes

    Minor

    The Results say no oligomer-positive puncta were present at five minutes under basal or stimulated conditions, but the Figure 3 legend says a low number of A11-positive structures were observed at five minutes without KCl.

2 of 2

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References 68 · Cited by 232

Authors
Deshpande, A., Kawai, H., Metherate, R., Glabe, C. G., & Busciglio, J.
Affiliations
University of California, Irvine (US)
Corresponding author
Busciglio, Jorge
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2009-04-01
Volume
29
Issue
13
Pages
4004-4015
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.5980-08.2009
PMC
PMC6665357
OpenAlex
W1963885312
Cited by
232
References
68
Citations by year
2026: 5 · 2025: 5 · 2024: 9 · 2023: 11 · 2022: 6 · 2021: 4 · 2020: 9 · 2019: 9 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 10 · 2014: 19 · 2013: 16 · 2012: 30
FWCI
21.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • California Department of Public Health
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-38466, R01HD038466)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid-beta oligomers, synaptic zinc, excitatory synapses, Alzheimer's disease, ZnT3, clioquinol, NMDA receptor NR2B, synaptic loss, hippocampus, cortex
MeSH terms
Alzheimer Disease, Animals, Brain, Calmodulin-Binding Proteins, Carrier Proteins, Cells, Cultured, Drug Interactions, Female, Hippocampus, Humans, Membrane Proteins, Neurons, Potassium Chloride, Synapses, Tetrodotoxin, Time Factors, Zinc, Amyloid beta-Peptides, Synaptophysin, Rats, Sprague-Dawley, Mice, Knockout, Excitatory Amino Acid Antagonists, Glutamic Acid, Membrane Transport Proteins, Cation Transport Proteins, Mice, Rats, In Vitro Techniques

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