Oligomeric Amyloid-β Inhibits the Proteolytic Conversion of Brain-derived Neurotrophic Factor (BDNF), AMPA Receptor Trafficking, and Classical Conditioning

Zhaoqing Zheng,Boris Sabirzhanov,Joyce Keifer

doi:10.1074/jbc.m110.150821

Zhaoqing Zheng, Boris Sabirzhanov + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m110.150821

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Abstract

Amyloid-β (Aβ) peptide is thought to have a significant role in the progressive memory loss observed in patients with Alzheimer disease and inhibits synaptic plasticity in animal models of learning. We previously demonstrated that brain-derived neurotrophic factor (BDNF) is critical for synaptic AMPA receptor delivery in an in vitro model of eyeblink classical conditioning. Here, we report that acquisition of conditioned responses was significantly attenuated by bath application of oligomeric (200 nm), but not fibrillar, Aβ peptide. Western blotting revealed that BDNF protein expression during conditioning is significantly reduced by treatment with oligomeric Aβ, as were phosphorylation levels of cAMP-response element-binding protein (CREB), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV), and ERK. However, levels of PKA and PKCζ/λ were unaffected, as was PDK-1. Protein localization studies using confocal imaging indicate that oligomeric Aβ, but not fibrillar or scrambled forms, suppresses colocalization of GluR1 and GluR4 AMPA receptor subunits with synaptophysin, indicating that trafficking of these subunits to synapses during the conditioning procedure is blocked. In contrast, coapplication of BDNF with oligomeric Aβ significantly reversed these findings. Interestingly, a tolloid-like metalloproteinase in turtle, tTLLs (turtle tolloid-like protein), which normally processes the precursor proBDNF into mature BDNF, was found to degrade oligomeric Aβ into small fragments. These data suggest that an Aβ-induced reduction in BDNF, perhaps due to interference in the proteolytic conversion of proBDNF to BDNF, results in inhibition of synaptic AMPA receptor delivery and suppression of the acquisition of conditioning.

Highlights

Characterized pathologically by the presence of senile plaques and intracellular neurofibrillary tangles
Representative abducens nerve recordings are shown from a preparation treated with 200 nM oligomeric A␤ that blocked the expression of Conditioned responses (CRs) but left the unconditioned response unaffected (Fig. 2A, left panel) and a preparation incubated with 200 nM fibrillar A␤ that exhibited conditioning (Fig. 2A, right panel, CR indicated by the arrow)
Effect of Oligomeric A␤ on Protein Kinase Phosphorylation during Conditioning—Previously [24, 25], we showed that PKA, calmodulin-dependent protein kinase II (CaMKII) and calmodulin-dependent protein kinase IV (CaMKIV), cAMP-response element-binding protein (CREB), extracellular signal-regulated kinase (ERK), and the ␨ isoform of PKC were activated during conditioning

Summary

Introduction

Characterized pathologically by the presence of senile plaques and intracellular neurofibrillary tangles. Conditioned responses (CRs) are accompanied by enhanced levels of BDNF protein, and application of BDNF alone induces synaptic delivery of GluR1- and GluR4-containing AMPA receptors through TrkB- and extracellular signal-regulated kinase (ERK)-mediated mechanisms [8, 9]. Preparations incubated with tTLLs alone expressed BDNF, whereas levels of BDNF significantly declined in the presence of A␤, suggesting that oligomeric A␤ competes with proBDNF as a target for cleavage by proteases. Together, these data suggest a novel mechanism whereby oligomeric A␤ inhibits AMPA receptor trafficking and conditioning by interfering with the extracellular proteolytic processing of proBDNF into mature BDNF

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