title: Transgenic mice overexpressing human acetylcholinesterase and the Swedish amyloid precursor protein mutation: effect of nicotine treatment.
abstract: Acetylcholinesterase (AChE) is shown to promote deposition of beta-amyloid (Abeta) peptides and to enhance Abeta 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 Abeta, 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 Abeta levels in single transgenic APPswe mice. Already at 1 and 3 months, hAChE-Tg// APPswe mice showed increased levels of cortical insoluble Abeta1-40 and Abeta1-42 compared with APPswe mice, whereas APPswe mice displayed increased soluble Abeta1-40. Abeta plaques were detected at 7 months, thus before onset of plaque formation in APPswe mice. No differences were found in [125I]alpha-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 Abeta1-40 levels, while both L(-)- and D(+)-nicotine (final dose 0.45 mg/kg) increased soluble Abeta1-42. 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]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 Abeta compared with APPswe mice, due to the possible interaction between Abeta and AChE-S, whereas APPswe mice exhibit increased soluble Abeta. The interaction between Abeta and AChE-S may also explain the different effect of nicotine on Abeta 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.
authors.affiliation: Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska University Hospital, Huddinge, Novum 5th Floor, S-141 86 Stockholm, Sweden.
authors.forename: M M
authors.initials: MM
authors.lastname: Hedberg
authors.forename: M M
authors.initials: MM
authors.lastname: Svedberg
authors.forename: T
authors.initials: T
authors.lastname: Mustafiz
authors.forename: W F
authors.initials: WF
authors.lastname: Yu
authors.forename: M
authors.initials: M
authors.lastname: Mousavi
authors.forename: Z Z
authors.initials: ZZ
authors.lastname: Guan
authors.forename: C
authors.initials: C
authors.lastname: Unger
authors.forename: A
authors.initials: A
authors.lastname: Nordberg
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic; D016708:Synaptophysin / Q000096:biosynthesis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D016564:Amyloid beta-Protein Precursor; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D016708:Synaptophysin; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D000110:Acetylcholinesterase