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

Article type: Research Article

Authors: Utsuki, Tadanobu^a | Shoaib, Mohammed^b | Holloway, Harold W.^a | Ingram, Donald K.^a | Wallace, William C.^a | Haroutunian, Vahram^c | Sambamurti, Kumar^d | Lahiri, Debomoy K.^e | Greig, Nigel H.^{a; *}

Affiliations: [a] Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Dr., Baltimore, MD 21224, USA | [b] Behavioural Pharmacology Section, Institute of Psychiatry, London SE5 8AF, England, UK | [c] Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA | [d] Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA | [e] Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Correspondence: [*] Corresponding author: Nigel H. Greig, Drug Design & Development Section, LNS, Gerontology Research Center, 5600 Nathan Shock Dr., Baltimore, MD 21224, USA. Tel.: +1 410 558 8278; Fax: +1 410 558 8323; E-mail: [email protected].

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. Over-production 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 βPP by a group of secretases. AβPP cleavage by γ-secretase results in the secretion of a truncated soluble βPP (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 sAPPγlevels 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 Aβdeposition.

Keywords: Nicotine drug abuse, Alzheimer's dementia, amyloid, β-peptide, cholinergic system, scopolamine, smoking, neuroprotection

DOI: 10.3233/JAD-2002-4507

Journal: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 405-415, 2002