Elsevier

Neuroscience

Volume 127, Issue 3, 2004, Pages 563-567
Neuroscience

Rapid Report
Inhibition of nicotinic acetylcholine receptors by apolipoprotein E-derived peptides in rat hippocampal slices

https://doi.org/10.1016/j.neuroscience.2004.05.045Get rights and content

Abstract

Apolipoprotein E (ApoE) is a well-known genetic risk factor for Alzheimer's disease (AD). Dysfunctions in cholinergic signaling, and in particular in the function of neuronal nicotinic acetylcholine receptors (nAChRs), have also been linked with AD and cognition. To address whether there is a link between ApoE and nAChR function, we used electrophysiological techniques to test the effects of synthetic ApoE-mimetic peptides derived from the low-density lipoprotein receptor (LDLR) binding domain for the ability to modulate nAChR activity in hippocampal interneurons. ApoE133–149 completely inhibited ACh-evoked responses in a dose-dependent manner, yielding an IC50 value of 720±70 nM. A shorter peptide spanning residues 141–148 mimicked this effect while a second peptide spanning residues 133–140 was without effect, indicating that the arginine-rich domain is responsible for nAChR interaction. Inhibition of ACh-evoked responses was voltage-independent, and displayed partial receptor specificity as no effect on glycine- or GABA-evoked responses occurred. These results demonstrate that peptides derived from the LDLR binding domain of ApoE block the function of nAChRs in hippocampal slices, an interaction that may have implications for AD.

Section snippets

Peptide synthesis

ApoE-derived peptides were synthesized by Sigma-Genosys (The Woodlands, TX, USA) at a purity of 95% and reconstituted in sterile, deionized water yielding stock concentrations of 15–20 mM. Stock solutions were stored at −20 °C and diluted to desired concentrations on the day of the experiment. The peptides used in this study were acetylated at the amino terminus and amide-capped at the carboxyl terminus, except for ApoE133–140, which contained a free amino terminus. Pentalysine was purchased

Results

Synthetic peptides derived from the low-density lipoprotein receptor (LDLR) binding domain of ApoE have been shown to mimic actions of the holoprotein and serve as useful tools in exploring novel mechanisms of ApoE action (Marques and Crutcher, 2003). Accordingly, a 17 amino acid peptide containing residues 133–149 of ApoE (Ac-LRVRLASHLRKLRKRLL-NH2) was tested for the ability to modulate nAChR-mediated responses in rat hippocampal CA1 stratum radiatum interneurons from acutely isolated slices.

Discussion

The present study demonstrates that a peptide derived from the LDLR binding domain of ApoE inhibits α7-containing nAChRs in hippocampal slices at submicromolar concentrations, and that this activity is maintained within an eight residue fragment (ApoE141–148). While studies have shown that ApoE-derived peptides possess a number of biological functions ranging from neuroprotection (Aono et al., 2003) to neurotoxicity (Tolar et al., 1997), this represents the first electrophysiological study

Acknowledgements

We would like to thank S. Dudek and D. Armstrong for advice in preparing the manuscript.

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