A Role for Nicotinic Acetylcholine Receptors in Alzheimer's Disease

Science's STKE  26 Aug 2003:
Vol. 2003, Issue 197, pp. tw330-TW330
DOI: 10.1126/stke.2003.197.tw330

Neurofibrillary tangles, which contain a phosphorylated form of the microtubule-binding protein tau, and amyloid plaques, which contain the β-amyloid peptide Aβ1-42, are common in the brains of Alzheimer's disease patients. Wang et al. showed that cells that express α7 nicotinic acetylcholine receptors (α7nAChRs) exhibit a dose-dependent Aβ1-42 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 Aβ1-42, whereas cells that did not express α7nAChRs, 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 Aβ1-42 fragment and not other fragments of Aβ. Furthermore, tau phosphorylation in response to Aβ1-42 was inhibited by pharmacological treatments that selectively blocked α7nAChRs or inhibition of α7nAChR expression by oligonucleotide antisense treatment. Interestingly, Aβ1-42 exhibits inhibitory activity toward α7nAChR with respect to calcium mobilization and acetylcholine release; however, Wang et al. reported that Aβ1-42 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 α7nAChR. JNK-1 and ERK1/2 were able to phosphorylate tau in vitro. Thus, Aβ1-42 may contribute to tau phosphorylation through an α7nAChR pathway, further supporting a role for α7nAChRs in Alzheimer's disease progression.

H.-Y. Wang, W. Li, N. J. Benedetti, D. H. S. Lee, α7 Nicotinic acetylcholine receptors mediate β-amyloid peptide-induced tau protein phosphorylation. J. Biol. Chem. 278, 31547-31553 (2003). [Abstract] [Full Text]