Differential physiologic responses of alpha7 nicotinic acetylcholine receptors to beta-amyloid1-40 and beta-amyloid1-42.
The beta-amyloid peptides (Abeta), Abeta(1-40) and Abeta(1-42), have been implicated in Alzheimer's disease (AD) pathology. Although Abeta(1-42) is generally considered to be the pathological peptide in AD, both Abeta(1-40) and Abeta(1-42) have been used in a variety of experimental models without discrimination. Here we show that monomeric or oligomeric forms of the two Abeta peptides, when interact with the neuronal cation channel, alpha7 nicotinic acetylcholine receptors (alpha7nAChR), would result in distinct physiologic responses as measured by acetylcholine release and calcium influx experiments. While Abeta(1-42) effectively attenuated these alpha7nAChR-dependent physiology to an extent that was apparently irreversible, Abeta(1-40) showed a lower inhibitory activity that could be restored upon washings with physiologic buffers or treatment with alpha7nAChR antagonists. Our data suggest a clear pharmacological distinction between Abeta(1-40) and Abeta(1-42).
Lee
Daniel H S
DH
Biogen Inc., 14 Cambridge Ctr. Bio6, 660, Cambridge, Massachusetts 02142, USA. Daniel_Lee@Biogen.com
Wang
Hoau-Yan
HY
D000109:Acetylcholine / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020916:Conotoxins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000378:metabolism; D066298:In Vitro Techniques; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011807:Quinolizines; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013347:Subcellular Fractions; D013574:Synaptosomes / Q000378:metabolism; D000093843:Quinolizidine Alkaloids
D000109:Acetylcholine; D000470:Alkaloids; D016229:Amyloid beta-Peptides; D001285:Atropine; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium; D002121:Calcium Channel Blockers; D020916:Conotoxins; D018727:Muscarinic Antagonists; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011188:Potassium; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine