α4 but Not α3 and α7 Nicotinic Acetylcholine Receptor Subunits Are Lost from the Temporal Cortex in Alzheimer's Disease

Authors

  • C. M. Martin-Ruiz,

  • J. A. Court,

  • E. Molnar,

  • M. Lee,

  • C. Gotti,

  • A. Mamalaki,

  • T. Tsouloufis,

  • S. Tzartos,

  • C. Ballard,

  • R. H. Perry,

  • E. K. Perry


  • Abbreviation used : AD, Alzheimer's disease ; αBGT α-bungarotoxin ; nAChR, nicotinic acetylcholine receptor ; PVDF, polyvinylidene difluoride ; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis.

Address correspondence and reprint requests to Dr. C. M. Martin-Ruiz at MRC Neurochemical Pathology Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, U.K.

Abstract

Abstract : Neuronal nicotinic acetylcholine receptors labelled with tritiated agonists are reduced in the cerebral cortex in Alzheimer's disease (AD), but to date it has not been demonstrated which nicotinic receptor subunits contribute to this deficit. In the present study, autopsy tissue from the temporal cortex of 14 AD cases and 15 age-matched control subjects was compared using immunoblotting with antibodies against recombinant peptides specific for α3, α4, and α7 subunits, in conjunction with [3H]epibatidine binding. Antibodies to α3, α4, and α7 produced one major band on western blots at 59, 51, and 57 kDa, respectively. [3H]Epibatidine binding and α4-like immunoreactivity (using antibodies against the extracellular domain and cytoplasmic loop of the α4 subunit) were reduced in AD cases compared with control subjects (p <0.02) and with a subgroup of control subjects (n = 9) who did not smoke prior to death (p <0.05) for the former two parameters. [3H]Epibatidine binding and cytoplasmic α4-like immunoreactivity were significantly elevated in a subgroup of control subjects (n = 4) known to have smoked prior to death (p <0.05). There were no significant changes in α3- or α7-like immunoreactivity associated with AD or tobacco use. The selective involvement of α4 has implications for understanding the role of nicotinic receptors in AD and potential therapeutic targets.

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