Nicotine lowers the secretion of the Alzheimer's amyloid beta-protein precursor that contains amyloid beta-peptide in rat.
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 beta-protein precursor (AbetaPP) processing in rat. Over-production and/or altered metabolism of AbetaPP, resulting in increased amyloid beta-peptide (Abeta), appear pivotal in the pathogenesis of AD. Abeta is generated proteolytically from betaPP by a group of secretases. AbetaPP cleavage by gamma-secretase results in the secretion of a truncated soluble betaPP (sAPPgamma) that contains intact Abeta. 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 sAPPgamma. These actions were blocked by nicotinic receptor antagonism. Whereas nicotinic antagonists alone had no effect on either total sAPP or sAPPgammalevels in CSF, muscarinic antagonism significantly elevated them; suggesting that muscarinic rather than nicotinic receptor silence alters processing of AbetaPP to favor a potentially amyloidogenic route. Combined nicotine and muscarinic antagonism attenuated the action of the latter to elevate sAPPgamma, indicating that nicotine modifies AbetaPP processing away from potentially amyloidogenic products. These results suggest that within the brain, levels of total sAPP, sAPPgamma and, accordingly, Abeta are subject to cholinergic manipulation, offering therapeutic potential at the level of AbetaPP processing to decrease Abetadeposition.
Utsuki
Tadanobu
T
Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Dr., Baltimore, MD 21224, USA.
Shoaib
Mohammed
M
Holloway
Harold W
HW
Ingram
Donald K
DK
Wallace
William C
WC
Haroutunian
Vahram
V
Sambamurti
Kumar
K
Lahiri
Debomoy K
DK
Greig
Nigel H
NH
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors*; D000818:Animals; D005731:Ganglionic Stimulants / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D009538:Nicotine / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005731:Ganglionic Stimulants; D018696:Neuroprotective Agents; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D009538:Nicotine