Age-related impairment of synaptic transmission but normal long-term potentiation in transgenic mice that overexpress the human APP695SWE mutant form of amyloid precursor protein
Age-related impairment of synaptic transmission but normal long-term potentiation in transgenic mice that overexpress the human APP695SWE mutant form of amyloid precursor protein
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DOI：
10.1523/jneurosci.21-13-04691.2001
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发表时间：
2001-07-01
影响因子：
5.3
通讯作者：
Seabrook, GR
中科院分区：
文献类型：
--
作者：
Fitzjohn, SM;Morton, RA;Seabrook, GR
我们研究了一种与阿尔茨海默病（AD）相关的转基因小鼠品系的突触功能，该品系过度表达具有K670N和M671L突变的人淀粉样前体蛋白的695个氨基酸异构体（APP(695)SWE小鼠），这种突变与早发性家族性阿尔茨海默病有关。老年转基因小鼠的Aβ水平大幅升高（高达22 μmol/gm），并显示出特征性的Aβ斑块。与野生型同窝对照相比，12月龄APP(695)SWE转基因动物的海马切片在CA1区显示出突触传递水平降低。在制备脑切片过程中加入离子型谷氨酸受体拮抗剂犬尿喹啉酸可消除这种缺陷。在18月龄时，尽管使用了犬尿喹啉酸处理，但在CA1区仍观察到基础突触传递的选择性缺陷。在12月龄和18月龄时，APP(695)SWE转基因小鼠的双脉冲易化和长时程增强（LTP）均正常。因此，尽管老年APP(695)SWE转基因小鼠的Aβ蛋白水平大幅升高、斑块数量增加且基础突触传递降低，但LTP仍可正常诱导和表达。我们得出结论，对兴奋性毒性的易感性增加，而非对LTP的特定影响，是APP(695)SWE小鼠认知缺陷的主要原因。
We have studied synaptic function in a transgenic mouse strain relevant to Alzheimer's disease (AD), overexpressing the 695 amino acid isoform of human amyloid precursor protein with K670N and M671L mutations (APP(695)SWE mice), which is associated with early-onset familial AD. Aged-transgenic mice had substantially elevated levels of A beta (up to 22 mu mol/gm) and displayed characteristic A beta plaques. Hippocampal slices from 12-month-old APP(695)SWE transgenic animals displayed reduced levels of synaptic transmission in the CA1 region when compared with wild-type littermate controls. Inclusion of the ionotropic glutamate receptor antagonist kynurenate during preparation of brain slices abolished this deficit. At 18 months of age, a selective deficit in basal synaptic transmission was observed in the CA1 region despite treatment with kynurenate. Paired-pulse facilitation and long-term potentiation (LTP) were normal in APP(695)SWE transgenic mice at both 12 and 18 months of age. Thus, although aged APP(695)SWE transgenic mice have greatly elevated levels of A beta protein, increased numbers of plaques, and reduced basal synaptic transmission, LTP can still be induced and expressed normally. We conclude that increased susceptibility to excitotoxicity rather than a specific effect on LTP is the primary cause of cognitive deficits in APP(695)SWE mice.