Nicotine lowers the secretion of the Alzheimer's amyloid β-protein precursor that contains amyloid β-peptide in rat

Tadanobu Utsuki, Mohammed Shoaib, Harold W. Holloway, Donald K. Ingram, William C. Wallace, Vahram Haroutunian, Kumar Sambamurti, Debomoy K. Lahiri, Nigel H. Greig

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Reports of an inverse relationship between nicotine intake, due to cigarette smoking, and the incidence of Alzheimer's disease (AD) prompted us to investigate the effects of nicotine on amyloid β-protein precursor (AβPP) processing in rat. Overproduction and/or altered metabolism of AβPP, resulting in increased amyloid β-peptide (Aβ), appear pivotal in the pathogenesis of AD. Aβ is generated proteolytically from AβPP by a group of secretases. AβPP cleavage by γ-secretase results in the secretion of a truncated soluble AβPP (sAPPγ) that contains intact Aβ. Nicotine, 1 and 8 mg/kg/day, doses commensurate with cigarette smoking and a higher but well tolerated dose, respectively, was administered over 14 days and Western blot analysis was performed on sAPP fragments. Both doses significantly reduced sAPPγ. These actions were blocked by nicotinic receptor antagonism. Whereas nicotinic antagonists alone had no effect on either total sAPP or sAPPγ levels in CSF, muscarinic antagonism significantly elevated them; suggesting that muscarinic rather than nicotinic receptor silence alters processing of AβPP to favor a potentially amyloidogenic route. Combined nicotine and muscarinic antagonism attenuated the action of the latter to elevate sAPPγ, indicating that nicotine modifies AβPP processing away from potentially amyloidogenic products. These results suggest that within the brain, levels of total sAPP, sAPPγ and, accordingly, Aβ are subject to cholinergic manipulation, offering therapeutic potential at the level of AβPP processing to decrease Aβ deposition.

Original languageEnglish (US)
Pages (from-to)405-415
Number of pages11
JournalJournal of Alzheimer's Disease
Volume4
Issue number5
DOIs
StatePublished - Oct 2002

Keywords

  • β-peptide
  • Alzheimer's dementia
  • Amyloid
  • Cholinergic system
  • Neuroprotection
  • Nicotine drug abuse
  • Scopolamine
  • Smoking

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology

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