Increased levels of tau protein in SH-SY5Y cells after treatment with cholinesterase inhibitors and nicotinic agonists.
Several cholinesterase inhibitors used in the treatment of Alzheimer's disease (AD) have been shown to interact with an allosteric site on the nicotinic acetylcholine receptor (nAChR). A possible linkage between the phosphorylation state of tau, the major component of paired helical filaments found in AD brain, and stimulation of nAChRs by cholinesterase inhibitors and nicotinic agonists was investigated. Western blot analysis showed that treatment of SH-SY5Y cells for 72 h with the cholinesterase inhibitors tacrine (10(-5) M), donepezil (10(-5) M), and galanthamine (10(-5) M), nicotine (10(-5) M), and epibatidine (10(-7) M) increased tau levels as detected with Tau-1, AT 8, and AT 270 monoclonal antibodies and binding of [3H]epibatidine. The increase in tau immunoreactivity induced by nicotine, epibatidine, and tacrine, but not the up-regulation of nAChRs, was prevented by the antagonists d-tubocurarine and mecamylamine. Both antagonists were synergistic with the nicotinic agonists in causing up-regulation, but only d-tubocurarine showed a synergistic effect with tacrine. The increased tau immunoreactivity induced by tacrine was not prevented by atropine, indicating that in terms of cholinergic receptors, tacrine modulates tau levels mainly through interactions with nAChRs and not with muscarinic receptors. Additional work is needed to determine the exact mechanism by which cholinesterase inhibitors and nicotinic agonists modulate phosphorylation and levels of tau protein.
Hellström-Lindahl
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E
Department of Clinical Neuroscience, Occupational Therapy, and Elderly Care Research, Karolinska Institute, Huddinge University Hospital, Sweden. Ewa.Hellstrom-Lindahl@kfcmail.hs.sll.se
Moore
H
H
Nordberg
A
A
D000469:Alkaline Phosphatase / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003470:Culture Media / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000378:metabolism*
D002800:Cholinesterase Inhibitors; D003470:Culture Media; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D016875:tau Proteins; D009538:Nicotine; D001285:Atropine; D000469:Alkaline Phosphatase; D002118:Calcium