A Role for Nicotinic Acetylcholine Receptors in Alzheimer's Disease

Abstract

Neurofibrillary tangles, which contain a phosphorylated form of the microtubule-binding protein tau, and amyloid plaques, which contain the β-amyloid peptide Aβ 1-42 , are common in the brains of Alzheimer's disease patients. Wang et al. showed that cells that express α 7 nicotinic acetylcholine receptors (α 7 nAChRs) exhibit a dose-dependent Aβ 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 Aβ 1-42 , whereas cells that did not express α 7 nAChRs, 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 Aβ 1-42 fragment and not other fragments of Aβ. Furthermore, tau phosphorylation in response to Aβ 1-42 was inhibited by pharmacological treatments that selectively blocked α 7 nAChRs or inhibition of α 7 nAChR expression by oligonucleotide antisense treatment. Interestingly, Aβ 1-42 exhibits inhibitory activity toward α 7 nAChR with respect to calcium mobilization and acetylcholine release; however, Wang et al. reported that Aβ 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 α 7 nAChR. JNK-1 and ERK1/2 were able to phosphorylate tau in vitro. Thus, Aβ 1-42 may contribute to tau phosphorylation through an α 7 nAChR pathway, further supporting a role for α 7 nAChRs in Alzheimer's disease progression. H.-Y. Wang, W. Li, N. J. Benedetti, D. H. S. Lee, α 7 Nicotinic acetylcholine receptors mediate β-amyloid peptide-induced tau protein phosphorylation. J. Biol. Chem. 278 , 31547-31553 (2003). [Abstract] [Full Text]