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

Acetylcholinesterase (AChE) is shown to promote deposition of β-amyloid (Aβ) peptides and to enhance Aβ 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 Aβ, 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 Aβ levels in single transgenic APPswe mice. Already at 1 and 3 months, hAChE-Tg//APPswe mice showed increased levels of cortical insoluble Aβ1-40 and Aβ1-42 compared with APPswe mice, whereas APPswe mice displayed increased soluble Aβ1-40. Aβ plaques were detected at 7 months, thus before onset of plaque formation in APPswe mice. No differences were found in [125I]α-bungarotoxin binding sites or hippocampal glial fibrillary acidic protein (GFAP) immunoreactivity between hAChE-Tg//APPswe, and APPswe mice at either 1 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 Aβ1-40 levels, while both l(−)- and d(+)-nicotine (final dose 0.45 mg/kg) increased soluble Aβ1-42. 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 [125I]α-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 Aβ compared with APPswe mice, due to the possible interaction between Aβ and AChE-S, whereas APPswe mice exhibit increased soluble Aβ. The interaction between Aβ and AChE-S may also explain the different effect of nicotine on Aβ 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.