β-Amyloid Impairs AMPA Receptor Trafficking and Function by Reducing Ca2+/Calmodulin-dependent Protein Kinase II Synaptic Distribution

Zhenglin Gu,Wenhua Liu,Zhen Yan

doi:10.1074/jbc.m806508200

Abstract

A fundamental feature of Alzheimer disease (AD) is the accumulation of beta-amyloid (Abeta), a peptide generated from the amyloid precursor protein (APP). Emerging evidence suggests that soluble Abeta oligomers adversely affect synaptic function, which leads to cognitive failure associated with AD. The Abeta-induced synaptic dysfunction has been attributed to the synaptic removal of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (AMPARs); however, it is unclear how Abeta induces the loss of AMPARs at the synapses. In this study we have examined the potential involvement of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), a signaling molecule critical for AMPAR trafficking and function. We found that the synaptic pool of CaMKII was significantly decreased in cortical neurons from APP transgenic mice, and the density of CaMKII clusters at synapses was significantly reduced by Abeta oligomer treatment. In parallel, the surface expression of GluR1 subunit as well as AMPAR-mediated synaptic response and ionic current was selectively decreased in APP transgenic mice and Abeta-treated cultures. Moreover, the reducing effect of Abeta on AMPAR current density was mimicked and occluded by knockdown of CaMKII and blocked by overexpression of CaMKII. These results suggest that the Abeta-induced change in CaMKII subcellular distribution may underlie the removal of AMPARs from synaptic membrane by Abeta.

Highlights

Because calmodulindependent protein kinase II (CaMKII) located in postsynaptic sites plays a crucial role in synaptic plasticity through the regulation of postsynaptic amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors [22, 34, 35], in this study we have examined the possibility that synaptic CaMKII is reduced by A␤, which underlies the A␤-induced decrease of AMPAR delivery to synapses
We further examined the change of CaMKII in amyloid precursor protein (APP) transgenic mice at different time points
AMPAR-mediated Synaptic Transmission and Ionic Current Are Impaired by A␤—Given the decreased level of surface GluR1 in APP mice, we investigated whether AMPAR-mediated synaptic currents are impaired in APP mice

Summary

Introduction

Similar to ␣-CaMKII, ␤-CaMKII in APP mice was not sites in APP transgenic mice might result in changes in the altered in the total level but was significantly decreased in P2 AMPAR phosphorylation and surface expression. Because biochemical assays showed that the level of surface GluR1 was selectively reduced in APP transgenic mice and in A␤-treated cultures, we performed immunocytochemical experiments to test the impact of A␤ on GluR1 located at synaptic membrane.

Results

Conclusion