title: Modulation of α7 nicotinic acetylcholine receptor and fibrillar amyloid-β interactions in Alzheimer's disease brain.
abstract: The nicotinic receptors (nAChRs), which play a critical role in cognitive function, are impaired early in the course of Alzheimer's disease (AD). We have previously demonstrated that amyloid-β (Aβ) assemblies bind to α7 nAChRs and form complexes in AD brain, suggesting that this cooperative process may contribute to disruption of synaptic function in AD. In the current study, we further characterized the interaction between different nAChR subtypes and fibrillar Aβ by binding assays in postmortem brain from AD and control cases using a wide range of drugs with different molecular targets, including selective nAChR subtype agonists, and the amyloid ligand Pittsburgh compound B (PIB) that binds with high (nanomolar) affinity to fibrillar Aβ. The α7 nAChR agonists varenicline and JN403, but not the α4β2 nAChR agonist cytisine, increased the 3H-PIB binding in autopsy tissue homogenates from AD and control frontal cortex. This effect was blocked in the presence of the α7 nAChR antagonists methyllycaconitine, α-bungarotoxin, and mecamylamine, but not by the α4β2 nAChR antagonist dihydro-β-erythroidine. Increases in (3)H-PIB binding evoked by varenicline and JN403 were also prevented by pre-incubation with another amyloid ligand, BF-227. The acetylcholinesterase inhibitor and allosteric nAChR modulator galantamine as well as the N-methyl-d-aspartate receptor blocker memantine did not significantly alter (3)H-PIB binding levels in AD brain. The present findings further support a specific interaction between fibrillar Aβ and α7 nAChRs in the brain, suggesting that treatment with α7 nAChR stimulatory drugs can modulate Aβ/α7 nAChR pathogenic signaling mechanisms in AD brain.
authors.affiliation: Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ruiqing
authors.initials: R
authors.lastname: Ni
authors.forename: Amelia
authors.initials: A
authors.lastname: Marutle
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds / Q000493:pharmacokinetics; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D018678:Cholinergic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005625:Frontal Lobe / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D011485:Protein Binding / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013844:Thiazoles / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D018678:Cholinergic Agents; C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D013844:Thiazoles; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014316:Tritium