Cited by 188Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Inhibition of Calcineurin-mediated Endocytosis and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Prevents Amyloid β Oligomer-induced Synaptic Disruption

Open access
Zhao, Wei-Qin, Santini, Francesca, Breese, Robert, Ross, Dave, Zhang, Xiaohua Douglas, Stone, David J., Ferrer, Marc, Townsend, Matthew +5 more·2010·Journal of Biological Chemistry

Abstract

Synaptic degeneration, including impairment of synaptic plasticity and loss of synapses, is an important feature of Alzheimer disease pathogenesis. Increasing evidence suggests that these degenerative synaptic changes are associated with an accumulation of soluble oligomeric assemblies of amyloid beta (Abeta) known as ADDLs. In primary hippocampal cultures ADDLs bind to a subpopulation of neurons. However the molecular basis of this cell type-selective interaction is not understood. Here, using siRNA screening technology, we identified alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits and calcineurin as candidate genes potentially involved in ADDL-neuron interactions. Immunocolocalization experiments confirmed that ADDL binding occurs in dendritic spines that express surface AMPA receptors, particularly the calcium-impermeable type II AMPA receptor subunit (GluR2). Pharmacological removal of the surface AMPA receptors or inhibition of AMPA receptors with antagonists reduces ADDL binding. Furthermore, using co-immunoprecipitation and photoreactive amino acid cross-linking, we found that ADDLs interact preferentially with GluR2-containing complexes. We demonstrate that calcineurin mediates an endocytotic process that is responsible for the rapid internalization of bound ADDLs along with surface AMPA receptor subunits, which then both colocalize with cpg2, a molecule localized specifically at the postsynaptic endocytic zone of excitatory synapses that plays an important role in activity-dependent glutamate receptor endocytosis. Both AMPA receptor and calcineurin inhibitors prevent oligomer-induced surface AMPAR and spine loss. These results support a model of disease pathogenesis in which Abeta oligomers interact selectively with neurotransmission pathways at excitatory synapses, resulting in synaptic loss via facilitated endocytosis. Validation of this model in human disease would identify therapeutic targets for Alzheimer disease.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1074/jbc.m109.057182

Cites

85 of 85 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Aβ oligomers interact with complexes containing the GluR2 subunit of AMPA receptors.

    “Co-immunoprecipitation and photoactivated amino acid cross-linking studies indicated that Aβ oligomers interact with complexes containing the GluR2 subunit of AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptors”
  • Pharmacological inhibition or removal of surface AMPA receptors reduced oligomer binding to neurons.

    “pharmacological inhibition or removal of surface AMPA receptors reduced oligomer binding to neurons (Zhao et al., 2010).”
  • Receptor downregulation has been extended to other plasticity-associated receptors, including EphB2 receptors, AMPA receptors, and insulin receptors.

    “Receptor downregulation has been extended to other plasticity-associated receptors, including EphB2 receptors (Lacor et al., 2007), AMPA-Rs (Jurgensen et al., 2011; Zhao et al., 2010), and insulin Rs (Zhao et al., 2008).”

Self-check

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

The self-check needs the paper’s full text.

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 9

  1. Gong, Y., Chang, L., Viola, K. L., Lacor, P. N., Lambert, M. P., Finch, C. E., Krafft, G. A., and Klein, W. L. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 10417-10422
  2. Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., Wals, P., Zhang, C., Finch, C. E., Krafft, G. A., and Klein, W. L. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 6448 -6453
  3. Ting, J. T., Kelley, B. G., Lambert, T. J., Cook, D. G., and Sullivan, J. M. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 353-358
  4. Chang, E. H., Savage, M. J., Flood, D. G., Thomas, J. M., Levy, R. B., Ma- hadomrongkul, V., Shirao, T., Aoki, C., and Huerta, P. T. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 3410 -3415
  5. Allen, P. B., Ouimet, C. C., and Greengard, P. (1997) Proc. Natl. Acad. Sci.
  6. Lamb, B. T., Sisodia, S. S., Lawler, A. M., Slunt, H. H., Kitt, C. A., Kearns, W. G., Pearson, P. L., Price, D. L., and Gearhart, J. D. (1993) Nat. Genet. 5, 22-30
  7. Walsh, D. M., Klyubin, I., Fadeeva, J. V., Rowan, M. J., and Selkoe, D. J. (2002) Biochem. Soc. Trans. 30, 552-557
  8. Biou, V., Bhattacharyya, S., and Malenka, R. C. (2008) Proc. Natl. Acad. Sci.
  9. Ono, K., Condron, M. M., and Teplow, D. B. (2009) Proc. Natl. Acad. Sci.

Cited by

Sorted by citations

Authors
Zhao, W.-Q., Santini, F., Breese, R., Ross, D., Zhang, X. D., Stone, D. J., Ferrer, M., Townsend, M., Wolfe, A. L., Seager, M. A., Kinney, G. G., Shughrue, P. J., & Ray, W. J.
Affiliations
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2010-03
Volume
285
Issue
10
Pages
7619-7632
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2045318822
Cited by
188
References
85
Citations by year
2026: 4 · 2025: 7 · 2024: 13 · 2023: 11 · 2022: 10 · 2021: 15 · 2020: 9 · 2019: 11 · 2018: 14 · 2017: 16 · 2016: 11 · 2015: 8 · 2014: 17 · 2013: 5 · 2012: 12
FWCI
8.17
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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, calcineurin, AMPA receptors, GluR2, receptor internalization, synaptic loss, dendritic spines, excitatory synapses, Alzheimer's disease, siRNA screening
MeSH terms
Animals, Cells, Cultured, Endocytosis, Hippocampus, Humans, Synapses, Amyloid beta-Peptides, Rats, Sprague-Dawley, Receptors, AMPA, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Calcineurin, Protein Subunits, RNA, Small Interfering, Rats, Protein Multimerization

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review