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Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid β oligomer-induced synaptic disruption
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.
2010-03-05
Source PublicationJournal of Biological Chemistry
ISSN00219258 1083351X
Volume285Issue:10Pages:7619-7632
AbstractSynaptic 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 β (Aβ) 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 α-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.Wedemonstrate that calcineurin mediates an endocytotic process that is responsible for the rapid internalization of bound ADDLs along with surfaceAMPAreceptor 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 Aβ 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. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI10.1074/jbc.M109.057182
URLView the original
Language英語
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Cited Times [WOS]:117   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
AffiliationMerck Research Laboratories
Recommended Citation
GB/T 7714
Zhao W.-Q.,Santini F.,Breese R.,et al. Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid β oligomer-induced synaptic disruption[J]. Journal of Biological Chemistry,2010,285(10):7619-7632.
APA Zhao W.-Q..,Santini F..,Breese R..,Ross D..,Zhang X.D..,...&Ray W.J..(2010).Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid β oligomer-induced synaptic disruption.Journal of Biological Chemistry,285(10),7619-7632.
MLA Zhao W.-Q.,et al."Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid β oligomer-induced synaptic disruption".Journal of Biological Chemistry 285.10(2010):7619-7632.
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