Inhibition of Calcineurin-mediated Endocytosis and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Prevents Amyloid β Oligomer-induced Synaptic Disruption
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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.
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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”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Zhao et al., 2010
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).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as 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).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Zhao et al., 2010
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- 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)
- PMC
- PMC2844209
- 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
- hybrid
- doi.org
- Licence
- 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.
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