Institute of Pathology - Laboratory of Neuropathology, University of Ulm, Ulm, Germany.
Acta Neuropathol Commun. 2013 Nov 18;1(1):77. doi: 10.1186/2051-5960-1-77.
The deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether Aβ always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses Aβ1-42 with a signal sequence in neurons. These animals produce intracellular Aβ independent of amyloid precursor protein (APP) but do not develop extracellular Aβ plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular Aβ plaques and intracellular Aβ aggregates.
Tracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in APP48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old APP23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old APP23 but not in 3- and 18-month-old APP48 mice. Frontocentral neurons of 18-month-old APP48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and APP23 mice. Aβ was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level.
These results indicate that APP-independent intracellular Aβ accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular Aβ pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aβ aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of Aβ may, thereby, play a role for the degeneration of neurites and synapses.
淀粉样 β-肽（Aβ）在大脑中的沉积是阿尔茨海默病（AD）的标志之一。目前尚不清楚 Aβ 是否总是导致类似的变化，或者它是否会因细胞内和/或细胞外定位或细胞内运输途径的不同而诱导不同的神经退行性特征。为了解决这个问题，我们分析了两种转基因小鼠模型：APP48 和 APP23 小鼠。APP48 小鼠在神经元中表达带有信号序列的 Aβ1-42。这些动物产生与淀粉样前体蛋白（APP）无关的细胞内 Aβ，但不形成细胞外 Aβ 斑块。APP23 小鼠在神经元中过度表达具有瑞典突变（KM670/671NL）的人 APP，并产生 APP 衍生的细胞外 Aβ 斑块和细胞内 Aβ 聚集体。
用 DiI 示踪剂追踪额前皮质 III 层的连合神经元，与同窝对照相比，APP48 小鼠没有发现树突退化的形态学迹象。相比之下，15 月龄 APP23 小鼠的高度分支的额前皮质连合神经元树突发生改变。3 月龄和 15 月龄 APP23 但不是 3 月龄和 18 月龄 APP48 小鼠额前皮质的不对称突触密度降低。与野生型和 APP23 小鼠相比，18 月龄 APP48 小鼠的胞体中的改变线粒体比例增加。在超微结构水平上，APP48 小鼠的神经元线粒体的膜中经常可见 Aβ。
这些结果表明，APP48 小鼠中独立于 APP 的细胞内 Aβ 积累与树突和神经突退化无关，但与线粒体改变有关，而 APP23 小鼠中 APP 衍生的细胞外和细胞内 Aβ 病理学与树突退化和突触丧失有关，而无明显的线粒体改变。因此，APP23 和 APP48 小鼠中的 Aβ 聚集体可能通过不同的机制诱导神经退行性变，并且 APP 相关的 Aβ 产生可能因此而发挥作用，导致神经突和突触的退化。
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