Papers in press in the Journal of Biological Chemistry and PNAS explore the relationship between Alzheimer's disease (AD) and nicotine.

In the June 11 JBC Papers in Press, principal author Daniel Lee and colleagues at Biogen Inc., Cambridge, Massachusetts, show that the α7-type nicotinic acetylcholine receptor (α7nAChR), the Aβ peptide, and the microtubule-associated protein tau are inextricably linked. Lee and colleagues had reported previously that Aβ has a novel action, namely, that it can bind to the α7nAChR receptor (see Wang et al., 2000). Aβ forms plaques on the extracellular spaces, whereas tau is found, in a hyperphosphorylated form, in the neurofibrillary tangles (NFT) that gum up the internal workings of affected neurons. Many researchers believe that Aβ-either its early intracellular form or once it has reentered neurons after having first been secreted-somehow induces tau phosphorylation. Now, Lee and coworkers suggest that Aβ's binding to α7nAChR mediates this proposed link.

First author H-Y Wang and colleagues used neuroblastoma cells and hippocampal synaptosomes, both rich in α7nAChR, to test what happens after Aβ binds to the nicotinic receptor. The authors show that adding Aβ1-42 to these systems results in the phosphorylation of tau at serine 202, threonine 181, and threonine 231. Significantly, these modifications are also found in NFTs. To test if this effect is directly attributable to Aβ interaction with the nicotinic receptor, the authors blocked the latter with α-bungarotoxin. In the presence of the toxin, no tau phosphorylation was observed. In addition, Aβ42-1 did not elicit any tau kinase activity, indicating that the effect was specific for native Aβ.

Several kinases have been shown to phosphorylate tau, including glycogen synthase kinase-3β, CDK5, extracellular receptor kinases (ERKs), and P38 kinase (see ARF related news story and ARF news story). Wang and coworkers used antibodies that specifically recognize active forms of these enzymes to determine if any of them mediate Aβ-induced tau phosphorylation. The only active kinases detected were ERK1 and ERK2, which became fully activated after cells or synaptosomes were incubated with Aβ1-42 for 10 minutes. In addition, when the authors incubated tau, ATP, and ERK1 or ERK2 in a test tube, they found that tau was phosphorylated on serine 202 and threonine 181, but not threonine 231.

These results may explain why Aβ induces tangle formation (see ARF related news story). They also offer an explanation for the-debated and disputed-finding that smoking slows AD progression, because nicotine and Aβ must compete for the same receptor. Such competition for the receptor may also lead to synaptic transmission defects (see ARF related live discussion).

The second connection between Aβ and nicotine comes from researchers at The Scripps Institute, La Jolla, California. In Wednesday’s PNAS Early Edition online, Tobin Dickerson and principal author Kim Janda suggest that progression of the disease may be slowed not by nicotine, but by a derivative, nornicotine.

The authors have previously reported that this metabolite can catalyze a chemical reaction between protein lysine side chains and reducing sugars, such as glucose. To test if Aβ can be so modified, Dickerson and Janda mixed the protein, glucose, and nornicotine together in a test tube, then measured the extent of Aβ modification (termed glycation) and aggregation.

The authors used sophisticated NMR measurements, including pulsed-field gradient NMR, where molecules in the sample tube are separated by size, almost like an in-situ chromatograph, to determine if nornicotine does indeed bind to Aβ. This diffusion-ordered NMR spectroscopy, or DOSY, showed two distinct populations of nornicotine, one free in solution and one protein-bound, indicating that a covalent reaction has cemented the nicotine metabolite to Aβ.

To test the significance of this, the authors used thioflavin T fluorescence to measure fibrillogenesis. Dickerson reports that in the presence of nornicotine, Aβ fibril formation is reduced by almost 20 percent. The implication is that nornicotine, which is a major nicotine metabolite in the central nervous system, may prevent aggregation of Aβ. The study included no in-vivo experiments-such as comparison of plaque number in brains of AD patients who had smoked vs. those who had not, or administration of nornicotine to AβPP-transgenic mice. In vivo, numerous other proteins compete in chemical glycation reactions.—Tom Fagan


  1. Comment on Janda et al.
    There is a great deal of interest in the role that nicotine and its metabolites might play in potential therapies for Alzheimer's disease. This study from Tobin Dickerson and Kim Janda of the Skaggs Institute of Chemical Biology looks in detail at glycation of the amyloid b protein by a nicotine metabolite. The justification for this analysis was given as the existing evidence that nicotine exposure leads to delayed onset of Alzheimer's disease, citing one paper.

    This assertion needs addressing. The literature suggesting that there is a protective effect from smoking was based on animal studies and early epidemiological studies, mostly of case-control design. Case-control studies are subject to bias. Longitudinal studies are generally felt to provide a less biased result. The longitudinal studies of smoking and Alzheimer's disease have either produced no association (e.g., Doll et al., 2000), or overall increased risk (e.g., Tyas et al., 2003). The literature has been reviewed systematically by Almeida and colleagues, 2002, and a review of the impact of study design has been published relatively recently (Kukull, 2001).

    While laboratory results are of interest as they investigate possible molecular mechanisms, which may or may not bring therapeutic benefit, it is important that the full range of epidemiological evidence is provided for readers, rather than the single paper, which justifies the particular molecular approach.


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  2. I find these results interesting. Since I'm not an expert in Ab aggregation, I cannot comment on the experimental results, other than to say that they are very preliminary. Unfortunately, the epidemiology on smoking and AD is not uniformly in favor of it being protective, and there are many dissenting studies. In several studies, smoking increases the risk of AD (or of vascular dementia, or both).

    The AD field is collecting a mounting number of negative clinical trials which were designed to test risk factors (or protective factors) noted in observational studies. NSAIDs and estrogen are two key examples. Before attempting to try nornicotine in human studies, it would be interesting to see whether the antiaggregation effect in vitro corresponds to lowering of amyloid levels and burden in transgenic mice when the compound is given chronically.

    View all comments by Douglas Galasko

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  3. Finally United? Aβ Found to Influence Tangle Formation

Paper Citations

  1. . Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. J Neurochem. 2000 Sep;75(3):1155-61. PubMed.

Other Citations

  1. ARF related live discussion

Further Reading

No Available Further Reading

Primary Papers

  1. . Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. J Biol Chem. 2003 Aug 22;278(34):31547-53. PubMed.
  2. . Glycation of the amyloid beta-protein by a nicotine metabolite: a fortuitous chemical dynamic between smoking and Alzheimer's disease. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8182-7. PubMed.