PT - JOURNAL ARTICLE AU - Elaine A. Gay AU - Rebecca C. Klein AU - Jerrel L. Yakel TI - Apolipoprotein E-Derived Peptides Block α7 Neuronal Nicotinic Acetylcholine Receptors Expressed in <em>Xenopus</em> Oocytes AID - 10.1124/jpet.105.095505 DP - 2006 Feb 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 835--842 VI - 316 IP - 2 4099 - http://jpet.aspetjournals.org/content/316/2/835.short 4100 - http://jpet.aspetjournals.org/content/316/2/835.full SO - J Pharmacol Exp Ther2006 Feb 01; 316 AB - For decades, the pathology of Alzheimer's disease has been associated with dysfunction of cholinergic signaling; however, the cellular mechanisms by which nicotinic acetylcholine receptor (nAChR) function is impaired in Alzheimer's disease are as yet unknown. The most significant genetic risk factor for the development of Alzheimer's disease is inheritance of the ϵ4 allele of apolipoprotein E (apoE). Recent data have demonstrated the ability of apoE-derived peptides to inhibit nAChRs in rat hippocampus. In the current study, the functional interaction between nAChRs and apoE-derived peptides was investigated in Xenopus oocytes expressing selected nAChRs. Both a 17-amino acid peptide fragment, apoE133-149, and an eight-amino acid peptide, apoE141-148, were able to maximally block acetylcholine (ACh)-mediated peak current responses for homomeric α7 nAChRs. ApoE peptide inhibition was dose-dependent and voltage- and activity-independent. The current findings suggest that apoE peptides are noncompetitive for acetylcholine and do not block functional α-bungarotoxin binding. ApoE peptides had a significantly decreased ability to inhibit ACh-mediated peak current responses for α4β2 and α2β2 nAChRs. Amino acid substitutions in the apoE peptide sequence suggest that the arginines are critical for peptide blockade of the α7 nAChR. The current data suggest that apoE fragments can disrupt nAChR signaling through a direct blockade of α7 nAChRs. These results may be useful in elucidating the mechanisms underlying memory loss and cognitive decline seen in Alzheimer's disease as well as aid in the development of novel therapeutics using apoE-derived peptides. The American Society for Pharmacology and Experimental Therapeutics