Functional interactions of fibrillar and oligomeric amyloid-β with alpha7 nicotinic receptors in Alzheimer's disease.
Amyloid-β (Aβ) peptides in the brain of patients with Alzheimer's disease (AD) assemble into various aggregation forms that differ in size, structure, and functional properties. Previous studies have shown that Aβ binds to nicotinic acetylcholine receptors (nAChRs) and activates signaling cascades that result in the disruption of synaptic functions. These findings suggest a possible link between impaired cholinergic neurotransmitter function in AD and Aβ pathogenesis. However, it is not yet known how the different Aβ assemblies interact with specific nAChR subtypes. In the present study, we demonstrate that neurotoxicity in neuronal cells in culture induced by fibrillar Aβ(1-40) is prevented through an α7 nAChR-dependent mechanism. The α7 nAChR agonists varenicline and JN403 increased binding of the amyloid ligand [³H]PIB to fibrillar Aβ in AD frontal cortex autopsy tissue. This suggests that the presence of nAChR agonists may inhibit interaction of Aβ with α7 nAChRs and prevent the formation of Aβ/α7 nAChR complexes. This interaction was confirmed in binding assays with [¹²⁵I]Aβ(1-40) and α7 nAChRs in autopsy brain tissue homogenates from the frontal cortex. The functional effects of Aβ fibrils and oligomers on nAChRs were examined by measuring intracellular calcium ([Ca(2+)](i) levels. Oligomeric, but not fibrillar Aβ(1-40), increased [Ca(2+)](i) in neuronal cells, and this effect was attenuated by varenicline. Our findings demonstrate that fibrillar Aβ exerts neurotoxic effects mediated partly through a blockade of α7 nAChRs, whilst oligomeric Aβ may act as a ligand activating α7 nAChRs, thereby stimulating downstream signaling pathways.
Karolinska Institutet, Division of Alzheimer Neurobiology, Department of Neurobiology, Care Sciences and Society, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Anna M
AM
Lilja
Omar
O
Porras
Elisa
E
Storelli
Agneta
A
Nordberg
Amelia
A
Marutle
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology; D016716:PC12 Cells; D011810:Quinoxalines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D000068580:Varenicline; D064569:alpha7 Nicotinic Acetylcholine Receptor
C520400:(S)-(1-azabicyclo(2.2.2)oct-3-yl)carbamic acid (S)-1-(2-fluorophenyl) ethyl ester; D016229:Amyloid beta-Peptides; D001552:Benzazepines; D002219:Carbamates; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000068580:Varenicline