title: Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation.
abstract: The Alzheimer's disease pathogenic peptide, beta-amyloid42 (A beta 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 beta 42-induced tau phosphorylation. We show that A beta 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 (alpha 7nAChR) including serum-deprived human SK-N-MC neuroblastoma cells and hippocampal synaptosomes. Although alpha 7nAChR agonists induced similar phosphorylation, pretreatment with antisense-alpha 7nAChR oligonucleotides (in cells) or alpha 7nAChR antagonists (in cells and synaptosomes) attenuated A beta-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 beta 42, and their respective kinase inhibitors suppressed A beta-induced tau phosphorylation. More importantly, recombinant-activated ERKs and JNK-1 could differentially phosphorylate tau protein in vitro. Thus, the alpha 7nAChR may mediate A beta-induced tau protein phosphorylation via ERKs and JNK-1.
authors.affiliation: Department of Physiology & Pharmacology, City University of New York Medical School, New York, New York 10031,USA.
authors.forename: Hoau-Yan
authors.initials: HY
authors.lastname: Wang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Benedetti
authors.forename: Daniel H S
authors.initials: DH
authors.lastname: Lee
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001483:Base Sequence; D017931:DNA Primers; D006801:Humans; D010766:Phosphorylation; D011978:Receptors, Nicotinic / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D017931:DNA Primers; D011978:Receptors, Nicotinic; D016875:tau Proteins