Hedberg M M, Svedberg M M, Mustafiz T, Yu W F, Mousavi M, Guan Z Z, Unger C, Nordberg A
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.
Neuroscience. 2008 Mar 3;152(1):223-33. doi: 10.1016/j.neuroscience.2007.11.022.
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.
已证实乙酰胆碱酯酶（AChE）可促进β-淀粉样蛋白（Aβ）肽的沉积并增强Aβ毒性。将Tg2576（携带淀粉样前体蛋白瑞典突变体APPswe的转基因小鼠）与过表达人突触乙酰胆碱酯酶（AChE-S）的小鼠进行杂交（hAChE-Tg//APPswe），以研究在AChE-S持续影响下，1至10月龄小鼠脑内Aβ的作用。由于我们之前已表明尼古丁可显著降低单转基因APPswe小鼠的Aβ水平，因此也对这些小鼠进行了尼古丁治疗效果的评估。在1个月和3个月时，与APPswe小鼠相比，hAChE-Tg//APPswe小鼠的皮质不溶性Aβ1-40和Aβ1-42水平升高，而APPswe小鼠的可溶性Aβ1-40水平升高。在7个月时检测到Aβ斑块，因此早于APPswe小鼠斑块形成的起始时间。在1个月或10月龄时，hAChE-Tg//APPswe小鼠与APPswe小鼠之间，[125I]α-银环蛇毒素结合位点或海马胶质纤维酸性蛋白（GFAP）免疫反应性均未发现差异。对14月龄的hAChE-Tg//APPswe小鼠每日两次给予L(-)-尼古丁（终剂量0.45mg/kg），持续10天，可增加皮质不溶性Aβ1-40水平，而L(-)-尼古丁和D(+)-尼古丁（终剂量0.45mg/kg）均可增加可溶性Aβ1-42水平。L(-)-尼古丁可降低hAChE-Tg//APPswe小鼠和非转基因对照小鼠海马的GFAP免疫反应性，而D(+)-尼古丁仅在hAChE-Tg//APPswe小鼠中引起降低。此外，D(+)-尼古丁可增加hAChE-Tg//APPswe小鼠海马和皮质中的[125I]α-银环蛇毒素结合位点。总之，由于Aβ与AChE-S之间可能存在相互作用，与APPswe小鼠相比，hAChE-Tg//APPswe小鼠在非常年幼时就表现出聚集性Aβ水平升高，而APPswe小鼠则表现出可溶性Aβ升高。Aβ与AChE-S之间的相互作用也可能解释尼古丁对hAChE-Tg//APPswe小鼠Aβ病理学的不同影响。本研究结果强调了使用不同转基因小鼠模型评估治疗阿尔茨海默病新药候选物效果的重要性。
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