NEUROSCIENCE A Role for Nicotinic Acetylcholine Receptors in Alzheimer's Disease

Neurofibrillary tangles, which contain a phosphorylated form of the microtubule-binding protein tau, and amyloid plaques, which contain the ß-amyloid peptide Aß_1-42, are common in the brains of Alzheimer's disease patients. Wang et al. showed that cells that express ₇ nicotinic acetylcholine receptors (₇nAChRs) exhibit a dose-dependent Aß_1-42 stimulation of tau phosphorylation at all three residues commonly phosphorylated in tau found in neurofibrillary tangles. Specifically, cortical and hippocampal synaptosomes and human neuroblastoma SK-N-MC cells responded to Aß_1-42, whereas cells that did not express ₇nAChRs, human Bowes melanoma cells and rat striatum synaptosomes, did not exhibit increased tau phosphorylation. The stimulation of tau phosphorylation was only observed in response to the Aß_1-42 fragment and not other fragments of Aß. Furthermore, tau phosphorylation in response to Aß_1-42 was inhibited by pharmacological treatments that selectively blocked ₇nAChRs or inhibition of ₇nAChR expression by oligonucleotide antisense treatment. Interestingly, Aß_1-42 exhibits inhibitory activity toward ₇nAChR with respect to calcium mobilization and acetylcholine release; however, Wang et al. reported that Aß_1-42 stimulated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase 1 (JNK-1). Furthermore, stimulation of these kinases was inhibited by antisense oligonucleotide treatment to decrease ₇nAChR. JNK-1 and ERK1/2 were able to phosphorylate tau in vitro. Thus, Aß_1-42 may contribute to tau phosphorylation through an ₇nAChR pathway, further supporting a role for ₇nAChRs in Alzheimer's disease progression.

H.-Y. Wang, W. Li, N. J. Benedetti, D. H. S. Lee, ₇ Nicotinic acetylcholine receptors mediate ß-amyloid peptide-induced tau protein phosphorylation. J. Biol. Chem. 278, 31547-31553 (2003). [Abstract] [Full Text]

The editors suggest the following Related Resources on Science sites:

VIRTUAL JOURNAL
₇ Nicotinic Acetylcholine Receptors Mediate -Amyloid Peptide-induced Tau Protein Phosphorylation

Hoau-Yan Wang, Weiwei Li, Nancy J. Benedetti, and Daniel H. S. Lee (22 August 2003)
J. Biol. Chem. 278 (34), 31547. [DOI: 10.1074/jbc.M212532200]
 |  Abstract »  |  Full Text »  |  PDF »