Increasing the Receptor Tyrosine Kinase EphB2 Prevents Amyloid-{beta}-induced Depletion of Cell-Surface Glutamate Receptors by a Mechanism that Requires EphB2’s PDZ-binding Motif and Neuronal Activity [Neurobiology]

November 20th, 2015 by Miyamoto, T., Kim, D., Knox, J. A., Johnson, E., Mucke, L.

Diverse lines of evidence suggest that amyloid-β peptides (Aβ) causally contribute to the pathogenesis of Alzheimer′s disease (AD), the most frequent neurodegenerative disorder. However, the mechanisms by which Aβ impairs neuronal functions remain to be fully elucidated. Previous studies showed that soluble Aβ oligomers interfere with synaptic functions by depleting NMDA-type glutamate receptors (NMDARs) from the neuronal surface and that overexpression of the receptor tyrosine kinase EphB2 can counteract this process. Through pharmacological treatments and biochemical analyses of primary neuronal cultures expressing wildtype or mutant forms of EphB2, we demonstrate that this protective effect of EphB2 depends on its PDZ-binding motif and the presence of neuronal activity, but not on its kinase activity. We further present evidence that EphB2′s protective effect may be mediated by the AMPA-type glutamate receptor (AMPAR) subunit GluA2, which can become associated with EphB2′s PDZ-binding motif through PDZ domain containing proteins and can promote the retention of NMDARs in the membrane. In addition, we show that the Aβ-induced depletion of surface NMDARs does not depend on several factors that have been implicated in the pathogenesis of Aβ-induced neuronal dysfunction, including aberrant neuronal activity, tau, prion protein (PrPC), and EphB2 itself. Thus, although EphB2 does not appear to be directly involved in the Aβ-induced depletion of NMDARs, increasing its expression may counteract this pathogenic process through a neuronal activity- and PDZ-dependent regulation of AMPARs.
  • Posted in Journal of Biological Chemistry, Publications
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