α7 nicotinic acetylcholine receptors mediate β-amyloid peptide-induced tau protein phosphorylation

The Alzheimer's disease pathogenic peptide, beta-amyloid(42) (Abeta(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 Abeta(42)-induced tau phosphorylation. We show that Abeta(42) elicited rapid and reversible tau protein phosphorylation on three proline-directed sites (Ser-202, Thr-181, and Thr-231) in systems enriched in alpha(7) nicotinic acetylcholine receptors (alpha7nAChR) including serum-deprived human SK-N-MC neuroblastoma cells and hippocampal synaptosomes. Although alpha7nAChR agonists induced similar phosphorylation, pretreatment with antisense-alpha7nAChR oligonucleotides (in cells) or alpha7nAChR antagonists (in cells and synaptosomes) attenuated Abeta-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 Abeta(42), and their respective kinase inhibitors suppressed Abeta-induced tau phosphorylation. More importantly, recombinant-activated ERKs and JNK-1 could differentially phosphorylate tau protein in vitro. Thus, the alpha7nAChR may mediate Abeta-induced tau protein phosphorylation via ERKs and JNK-1.