Nicotinic Acetylcholine Receptors Mediate -Amyloid Peptide-induced Tau Protein Phosphorylation*

The Alzheimer’s disease pathogenic peptide, -amyloid42 (A 42), induces tau protein phosphorylation. Because hyperphosphorylated tau is a consistent component of neurofibrillary tangles, a pathological hallmark of Alzheimer’s disease, we investigated the signaling molecules involved in A 42-induced tau phosphorylation. We show that A 42 elicited rapid and reversible tau protein phosphorylation on three proline-directed sites (Ser-202, Thr-181, and Thr-231) in systems enriched in 7 nicotinic acetylcholine receptors ( 7nAChR) including serum-deprived human SK-N-MC neuroblastoma cells and hippocampal synaptosomes. Although 7nAChR agonists induced similar phosphorylation, pretreatment with antisense7nAChR oligonucleotides (in cells) or 7nAChR antagonists (in cells and synaptosomes) attenuated A -induced tau phosphorylation. Western analyses showed that the mitogen-activated kinase cascade proteins, ERKs and c-Jun N-terminal kinase (JNK-1), were concomitantly activated by A 42, and their respective kinase inhibitors suppressed A -induced tau phosphorylation. More importantly, recombinant-activated ERKs and JNK-1 could differentially phosphorylate tau protein in vitro. Thus, the 7nAChR may mediate A induced tau protein phosphorylation via ERKs and JNK-1.