Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid β oligomer-induced synaptic disruption

Wei Qin Zhao, Francesca Santini, Robert Breese, Dave Ross, Xiaohua Douglas Zhang, David J. Stone, Marc Ferrer, Matthew Townsend, Abigail L. Wolfe, Matthew A. Seager, Gene G. Kinney, Paul J. Shughrue, William J. Ray

Research output: Contribution to journalArticlepeer-review

140 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)7619-7632
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number10
DOIs
StatePublished - Mar 5 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid β oligomer-induced synaptic disruption'. Together they form a unique fingerprint.

Cite this