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 dise ase (AD) have been shown to interact with an allosteric site on the nicotin ic acetylcholine receptor (nAChR), A possible linkage between the phosphory lation state of tau, the major component of paired helical filaments found in AD brain, and stimulation of nAChRs by cholinesterase inhibitors and nic otinic agonists was investigated. Western blot analysis showed that treatme nt 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 [H-3]epibatidine. The increase in tau immunoreactivity induced by nicotine, epibatidine, and tacrine, but not the up-regulation of nAChRs, was prevented by the antagoni sts d-tubocurarine and mecamylamine. Both antagonists were synergistic with the nicotinic agonists in causing up-regulation, but only d-tubocurarine s howed 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 inte ractions 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.