Inhibition of nicotinic acetylcholine receptors by apolipoprotein E-derived peptides in rat hippocampal slices.
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. ApoE(133-149) completely inhibited ACh-evoked responses in a dose-dependent manner, yielding an IC(50) 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.
Klein
R C
RC
Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
Yakel
J L
JL
D000544:Alzheimer Disease / Q000503:physiopathology; D000595:Amino Acid Sequence; D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry / Q000494:pharmacology*; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology*
D001057:Apolipoproteins E; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic