Transgenic mice overexpressing human acetylcholinesterase and the Swedish amyloid precursor protein mutation: Effect of nicotine treatment

Acetylcholinesterase (AChE) is shown to promote deposition of beta-amyloid (A beta) peptides and to enhance A beta toxicity. Tg2576 (transgenic mice carrying the Swedish mutation of amyloid precursor protein, APPswe) mice and mice overexpressing human synaptic acetylcholinesterase (AChE-S) were crossed (hAChE-Tg//APPswe), to study the effects of brain A beta, from 1 to 10 months of age, under the constant influence of AChE-S. The effect of nicotine treatment was also evaluated in these mice since we have previously shown that nicotine dramatically decreases A beta levels in single transgenic APPswe mice. Already at 1 and 3 months, hAChE-Tg// APPswe mice showed increased levels of cortical insoluble A beta 1 - 40 and A beta 1 - 42 compared with APPswe mice, whereas APPswe mice displayed increased soluble A beta 1 - 40. A beta plaques were detected at 7 months, thus before onset of plaque formation in APPswe mice. No differences were found in [I-125]alpha-bungarotoxin binding sites or hippocampal glial fibrillary acidic protein (GFAP) immunoreactivity between hAChE-Tg//APPswe, and APPswe mice at either I or 10 months of age. L( - )-Nicotine (final dose 0.45 mg/kg) treatment twice daily for 10 days to 14-month-old hAChE-Tg// APPswe mice increased cortical insoluble A beta 1 - 40 levels, while both L( - )- and D(+)-nicotine (final dose 0.45 mg/kg) increased soluble A beta 1 - 42. L( - )-Nicotine reduced hippocampal GFAP immunoreactivity both in hAChE-Tg//APPswe mice and non-transgenic controls, while D(+)-nicotine caused a decrease only in hAChE-Tg//APPswe mice. Moreover, D(+)nicotine increased the [I-125]alpha-bungarotoxin binding sites in the hippocampus, and cortex of the hAChE-Tg//APPswe mice. In conclusion, already at a very young age, hAChE-Tg// APPswe mice exhibit increased levels of aggregated A beta compared with APPswe mice, due to the possible interaction between A beta and AChE-S, whereas APPswe mice exhibit increased soluble A beta. The interaction between A beta and AChE-S may also explain the different effect of nicotine on A beta pathology in the hAChE-Tg//APPswe mice. The results in this study emphasize the importance of using different transgenic mouse models for evaluating the effect of new drug candidates for the treatment of Alzheimer's disease. (c) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.