Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (A beta) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of A beta peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve alpha(7)- and alpha(4)beta(2)-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of A beta-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day A beta(1-40)/A beta(1-42) or A beta(40-1) (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on A beta-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), A beta and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of A beta(1-40) and BACE1 peptides in hippocampal area CA1 and prevented A beta-induced impairment of learning and short-term memory. Chronic nicotine also prevented the A beta-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1 Furthermore, chronic nicotine treatment prevented the A beta-induced reduction of alpha(7)- and alpha(4)-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF). (C) 2009 Elsevier Inc. All rights reserved.