Both the D-(+) and L-(-) Enantiomers of Nicotine Inhibit Aβ Aggregation and Cytotoxicity

Susan A. Moore, Thomas N. Huckerby, Gillian L. Gibson, Nigel J. Fullwood, Stuart Turnbull, Brian J. Tabner, Omar Ali El-Agnaf, David Allsop

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The underlying cause of Alzheimer's disease is thought to be the aggregation of monomeric β-amyloid (Aβ), through a series of toxic oligomers, which forms the mature amyloid fibrils that accumulate at the center of senile plaques. It has been reported that L-(-)-nicotine prevents Aβ aggregation and toxicity, and inhibits senile plaque formation. Previous NMR studies have suggested that this could be due to the specific binding of L-(-)-nicotine to histidine residues (His6, His13, and His14) in the peptide. Here, we have looked at the effects of both of the L-(-) and D-(+) optical enantiomers of nicotine on the aggregation and cytotoxicity of Aβ(1-40). Surprisingly, both enantiomers inhibited aggregation of the peptide and reduced the toxic effects of the peptide on cells. In NMR studies with Aβ(1-40), both enantiomers of nicotine were seen to interact with the three histidine residues. Overall, our data indicate that nicotine can delay Aβ fibril formation and maintain a population of less toxic Aβ species. This effect cannot be due to a highly specific binding interaction between nicotine and Aβ, as previously thought, but could be due instead to weaker, relatively nonspecific binding, or to the antioxidant or metal chelating properties of nicotine. D-(+)-Nicotine, being biologically much less active than L-(-)-nicotine, might be a useful therapeutic agent.

Original languageEnglish
Pages (from-to)819-826
Number of pages8
JournalBiochemistry
Volume43
Issue number3
DOIs
Publication statusPublished - 27 Jan 2004
Externally publishedYes

Fingerprint

Enantiomers
Cytotoxicity
Nicotine
Agglomeration
Poisons
Amyloid Plaques
Histidine
Amyloid
Peptides
Nuclear magnetic resonance
Chelation
Oligomers
Toxicity
Alzheimer Disease
Antioxidants
Metals

ASJC Scopus subject areas

  • Biochemistry

Cite this

Moore, S. A., Huckerby, T. N., Gibson, G. L., Fullwood, N. J., Turnbull, S., Tabner, B. J., ... Allsop, D. (2004). Both the D-(+) and L-(-) Enantiomers of Nicotine Inhibit Aβ Aggregation and Cytotoxicity. Biochemistry, 43(3), 819-826. https://doi.org/10.1021/bi035728h

Both the D-(+) and L-(-) Enantiomers of Nicotine Inhibit Aβ Aggregation and Cytotoxicity. / Moore, Susan A.; Huckerby, Thomas N.; Gibson, Gillian L.; Fullwood, Nigel J.; Turnbull, Stuart; Tabner, Brian J.; Ali El-Agnaf, Omar; Allsop, David.

In: Biochemistry, Vol. 43, No. 3, 27.01.2004, p. 819-826.

Research output: Contribution to journalArticle

Moore, SA, Huckerby, TN, Gibson, GL, Fullwood, NJ, Turnbull, S, Tabner, BJ, Ali El-Agnaf, O & Allsop, D 2004, 'Both the D-(+) and L-(-) Enantiomers of Nicotine Inhibit Aβ Aggregation and Cytotoxicity', Biochemistry, vol. 43, no. 3, pp. 819-826. https://doi.org/10.1021/bi035728h
Moore SA, Huckerby TN, Gibson GL, Fullwood NJ, Turnbull S, Tabner BJ et al. Both the D-(+) and L-(-) Enantiomers of Nicotine Inhibit Aβ Aggregation and Cytotoxicity. Biochemistry. 2004 Jan 27;43(3):819-826. https://doi.org/10.1021/bi035728h
Moore, Susan A. ; Huckerby, Thomas N. ; Gibson, Gillian L. ; Fullwood, Nigel J. ; Turnbull, Stuart ; Tabner, Brian J. ; Ali El-Agnaf, Omar ; Allsop, David. / Both the D-(+) and L-(-) Enantiomers of Nicotine Inhibit Aβ Aggregation and Cytotoxicity. In: Biochemistry. 2004 ; Vol. 43, No. 3. pp. 819-826.
@article{7e6e4d9e51834dc7b5171e2255e9b813,
title = "Both the D-(+) and L-(-) Enantiomers of Nicotine Inhibit Aβ Aggregation and Cytotoxicity",
abstract = "The underlying cause of Alzheimer's disease is thought to be the aggregation of monomeric β-amyloid (Aβ), through a series of toxic oligomers, which forms the mature amyloid fibrils that accumulate at the center of senile plaques. It has been reported that L-(-)-nicotine prevents Aβ aggregation and toxicity, and inhibits senile plaque formation. Previous NMR studies have suggested that this could be due to the specific binding of L-(-)-nicotine to histidine residues (His6, His13, and His14) in the peptide. Here, we have looked at the effects of both of the L-(-) and D-(+) optical enantiomers of nicotine on the aggregation and cytotoxicity of Aβ(1-40). Surprisingly, both enantiomers inhibited aggregation of the peptide and reduced the toxic effects of the peptide on cells. In NMR studies with Aβ(1-40), both enantiomers of nicotine were seen to interact with the three histidine residues. Overall, our data indicate that nicotine can delay Aβ fibril formation and maintain a population of less toxic Aβ species. This effect cannot be due to a highly specific binding interaction between nicotine and Aβ, as previously thought, but could be due instead to weaker, relatively nonspecific binding, or to the antioxidant or metal chelating properties of nicotine. D-(+)-Nicotine, being biologically much less active than L-(-)-nicotine, might be a useful therapeutic agent.",
author = "Moore, {Susan A.} and Huckerby, {Thomas N.} and Gibson, {Gillian L.} and Fullwood, {Nigel J.} and Stuart Turnbull and Tabner, {Brian J.} and {Ali El-Agnaf}, Omar and David Allsop",
year = "2004",
month = "1",
day = "27",
doi = "10.1021/bi035728h",
language = "English",
volume = "43",
pages = "819--826",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - Both the D-(+) and L-(-) Enantiomers of Nicotine Inhibit Aβ Aggregation and Cytotoxicity

AU - Moore, Susan A.

AU - Huckerby, Thomas N.

AU - Gibson, Gillian L.

AU - Fullwood, Nigel J.

AU - Turnbull, Stuart

AU - Tabner, Brian J.

AU - Ali El-Agnaf, Omar

AU - Allsop, David

PY - 2004/1/27

Y1 - 2004/1/27

N2 - The underlying cause of Alzheimer's disease is thought to be the aggregation of monomeric β-amyloid (Aβ), through a series of toxic oligomers, which forms the mature amyloid fibrils that accumulate at the center of senile plaques. It has been reported that L-(-)-nicotine prevents Aβ aggregation and toxicity, and inhibits senile plaque formation. Previous NMR studies have suggested that this could be due to the specific binding of L-(-)-nicotine to histidine residues (His6, His13, and His14) in the peptide. Here, we have looked at the effects of both of the L-(-) and D-(+) optical enantiomers of nicotine on the aggregation and cytotoxicity of Aβ(1-40). Surprisingly, both enantiomers inhibited aggregation of the peptide and reduced the toxic effects of the peptide on cells. In NMR studies with Aβ(1-40), both enantiomers of nicotine were seen to interact with the three histidine residues. Overall, our data indicate that nicotine can delay Aβ fibril formation and maintain a population of less toxic Aβ species. This effect cannot be due to a highly specific binding interaction between nicotine and Aβ, as previously thought, but could be due instead to weaker, relatively nonspecific binding, or to the antioxidant or metal chelating properties of nicotine. D-(+)-Nicotine, being biologically much less active than L-(-)-nicotine, might be a useful therapeutic agent.

AB - The underlying cause of Alzheimer's disease is thought to be the aggregation of monomeric β-amyloid (Aβ), through a series of toxic oligomers, which forms the mature amyloid fibrils that accumulate at the center of senile plaques. It has been reported that L-(-)-nicotine prevents Aβ aggregation and toxicity, and inhibits senile plaque formation. Previous NMR studies have suggested that this could be due to the specific binding of L-(-)-nicotine to histidine residues (His6, His13, and His14) in the peptide. Here, we have looked at the effects of both of the L-(-) and D-(+) optical enantiomers of nicotine on the aggregation and cytotoxicity of Aβ(1-40). Surprisingly, both enantiomers inhibited aggregation of the peptide and reduced the toxic effects of the peptide on cells. In NMR studies with Aβ(1-40), both enantiomers of nicotine were seen to interact with the three histidine residues. Overall, our data indicate that nicotine can delay Aβ fibril formation and maintain a population of less toxic Aβ species. This effect cannot be due to a highly specific binding interaction between nicotine and Aβ, as previously thought, but could be due instead to weaker, relatively nonspecific binding, or to the antioxidant or metal chelating properties of nicotine. D-(+)-Nicotine, being biologically much less active than L-(-)-nicotine, might be a useful therapeutic agent.

UR - http://www.scopus.com/inward/record.url?scp=1642453817&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1642453817&partnerID=8YFLogxK

U2 - 10.1021/bi035728h

DO - 10.1021/bi035728h

M3 - Article

VL - 43

SP - 819

EP - 826

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 3

ER -