Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice
Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice
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DOI：
10.1523/jneurosci.22-02-00515.2002
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发表时间：
2002-01-15
影响因子：
5.3
通讯作者：
Jucker, M
中科院分区：
文献类型：
--
作者：
Bondolfi, L;Calhoun, M;Jucker, M
APP 23转基因小鼠表达突变的人淀粉样蛋白前体蛋白，并随着年龄的增长主要在新皮质和海马中逐渐形成淀粉样蛋白斑块，类似于阿尔茨海默病。我们以前曾报道过14至18个月大的APP 23小鼠海马CA 1区的神经元丢失。相比之下，在新皮层中没有发现神经元丢失。在本研究中，我们重新调查了成年和老年APP 23小鼠的新皮层神经元数量。令人惊讶的是，结果显示，与8个月大的野生型和27个月大的APP 23小鼠相比，8个月大的APP 23小鼠的新皮层神经元分别多出13%和14%。在27个月大的APP 23小鼠中，我们发现淀粉样蛋白负荷和神经元数量之间呈负相关。这些结果表明，APP 23小鼠有更多的神经元，直到他们发展淀粉样蛋白斑块，但随后在大脑淀粉样蛋白生成过程中失去神经元。支持这一观点，我们发现更多的神经元与坏死-凋亡表型在24个月大的APP 23小鼠的新皮层与年龄匹配的野生型小鼠相比。最近的报告表明，在小鼠新皮层靶向神经元死亡后的神经发生的刺激下，我们也研究了APP 23小鼠的神经发生。引人注目的是，我们发现，与年龄匹配的野生型小鼠和年轻的APP 23转基因小鼠相比，24个月大的APP 23小鼠中新产生的细胞增加了四到六倍。然而，随后的细胞表型分析显示，新皮层中没有一个新产生的细胞具有神经元表型。大多数是小胶质细胞，在较小程度上是星形胶质细胞。我们的结论是，在APP 23小鼠脑淀粉样变性引起适度的神经元损失，在新皮层和诱导显着的胶质细胞生成。
APP23 transgenic mice express mutant human amyloid precursor protein and develop amyloid plaques predominantly in neocortex and hippocampus progressively with age, similar to Alzheimer's disease. We have previously reported neuron loss in the hippocampal CA1 region of 14- to 18-month-old APP23 mice. In contrast, no neuron loss was found in neocortex. In the present study we have reinvestigated neocortical neuron numbers in adult and aged APP23 mice. Surprisingly, results revealed that 8-month-old APP23 mice have 13 and 14% more neocortical neurons compared with 8-month-old wild-type and 27-month-old APP23 mice, respectively. In 27-month-old APP23 mice we found an inverse correlation between amyloid load and neuron number. These results suggest that APP23 mice have more neurons until they develop amyloid plaques but then lose neurons in the process of cerebral amyloidogenesis. Supporting this notion, we found more neurons with a necrotic-apoptotic phenotype in the neocortex of 24-month-old APP23 mice compared with age-matched wild-type mice. Stimulated by recent reports that demonstrated neurogenesis after targeted neuron death in the mouse neocortex, we have also examined neurogenesis in APP23 mice. Strikingly, we found a fourfold to sixfold increase in newly produced cells in 24-month-old APP23 mice compared with both age-matched wildtype mice and young APP23 transgenic mice. However, subsequent cellular phenotyping revealed that none of the newly generated cells in neocortex had a neuronal phenotype. The majority were microglial and to a lesser extent astroglial cells. We conclude that cerebral amyloidosis in APP23 mice causes a modest neuron loss in neocortex and induces marked gliogenesis.