Cognitive correlates of Aβ deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes
Cognitive correlates of Aβ deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes
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DOI：
10.1016/j.brainres.2004.05.029
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发表时间：
2004-08-13
期刊：
影响因子：
2.9
通讯作者：
Gonzalez, MI
中科院分区：
文献类型：
--
作者：
Howlett, DR;Richardson, JC;Gonzalez, MI
几种阿尔茨海默病(AD)的转基因小鼠模型已经被开发出来，这些模型显示出β-淀粉样蛋白(Abeta)神经病理和行为缺陷。然而，并不是所有的研究都研究了认知障碍的发展与神经病理之间的关系。因此，我们利用物体识别实验研究了雄性和雌性APPswe X PS1.M146V(TASTPM)双突变转基因小鼠认知功能的时间变化，并将其与脑Aβ神经病理的发展相关联。在物体识别测试中，雄性和雌性TASTPM小鼠在6个月、8个月和10个月大时与野生型小鼠相比都表现出类似的显著认知障碍。在3个月或4个月大的时候，没有这种认知障碍。使用一组Abeta抗体的定量免疫组织化学显示，3个月大的小鼠首次出现大脑Abeta沉积，并随着年龄的增长而增加。双转基因TASTPM小鼠大脑Abeta沉积的早期出现支持了PS1基因突变加速Abeta沉积的证据。在所研究的所有年龄段，雌性TASTPM小鼠的脑Aβ负荷大于雄性TASTPM小鼠。在电子显微镜下，在6个月大的TASTPM小鼠的大脑皮质中首次观察到成熟的Abeta斑块，其中包括一个纤维核心，周围环绕着退化的神经突起和反应性胶质细胞，同一年龄的TASTPM小鼠出现明显的认知障碍。这些结果表明，TASTPM小鼠的认知障碍与神经连接的中断有关，而不是3个月前首次发生的Abeta沉积。(C)2004爱思唯尔B.V.保留所有权利。
Several transgenic mouse models of Alzheimer's disease (AD) have been developed that exhibit beta-amyloid (Abeta) neuropathology and behavioural deficits. However, not all studies have investigated the relationship between the development of cognitive impairment and neuropathology. Therefore, temporal changes in cognition were investigated in male and female double-mutant APPswe X PS1.M146V (TASTPM) transgenic mice using an object recognition test and correlated with the development of cerebral Abeta neuropathology. Both male and female TASTPM mice exhibited similar significant cognitive impairment at 6, 8 and 10 months of age in the object recognition test, compared to wild-type littermates. There was no such cognitive impairment at 3 or 4 months of age. Quantitative immunohistochemistry using a battery of Abeta antibodies demonstrated that cerebral Abeta deposition was first apparent in 3-month-old mice, and it increased with age. The early appearance of cerebral Abeta deposits in the double-transgenic TASTPM mice supports the evidence that mutations in the PS1 gene accelerate Abeta deposition. The cerebral Abeta load was greater in female than in male TASTPM mice at all ages investigated. In the electron microscope, mature Abeta plaques comprising a fibrillar core surrounded by degenerating neurites and reactive glia were first observed in the cortex of TASTPM mice at 6 months of age, the same age at which cognitive impairment became apparent. These results suggest that the cognitive impairment in TASTPM mice is related to the disruption of neural connectivity and not simply Abeta deposition, which first occurs 3 months earlier. (C) 2004 Elsevier B.V. All rights reserved.