Lysosomal network dysfunction is a prominent feature of Alzheimer's disease (AD). Although transgenic mouse models of AD are known to model some aspects of lysosomal network dysfunction, the lysosomal network has not yet been examined in the knock-in AppNL-G-F/NL-G-F mouse. We aimed to determine whether AppNL-G-F/NL-G-F mice exhibit disruptions to the lysosomal network in the brain. Lysosome-associated membrane protein 1 (LAMP1) and cathepsins B, L and D accumulated at amyloid beta plaques in the AppNL-G-F/NL-G-F mice, as occurs in human Alzheimer's patients. The accumulation of these lysosomal proteins occurred early in the development of neuropathology, presenting at the earliest and smallest amyloid beta plaques observed. AppNL-G-F/NL-G-F mice also exhibited elevated activity of β-hexosaminidase and cathepsins D/E and elevated levels of selected lysosomal network proteins, namely LAMP1, cathepsin D and microtubule-associated protein light chain 3 (LC3-II) in the cerebral cortex, as determined by western blot. Elevation of cathepsin D did not change the extent of co-localisation between cathepsin D and LAMP1 in the AppNL-G-F/NL-G-F mice. These findings demonstrate that perturbations of the lysosomal network occur in the AppNL-G-F/NL-G-F mouse model, further validating its use an animal model of pre-symptomatic AD.

中文翻译：

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阿尔茨海默氏病小鼠AppNL-GF / NL-GF模型中的溶酶体失调。

溶酶体网络功能障碍是阿尔茨海默氏病（AD）的突出特征。尽管已知AD的转基因小鼠模型可模拟溶酶体网络功能障碍的某些方面，但尚未在敲入的AppNL-GF / NL-GF小鼠中检查溶酶体网络。我们旨在确定AppNL-GF / NL-GF小鼠是否对大脑中的溶酶体网络有破坏作用。溶酶体相关的膜蛋白1（LAMP1）和组织蛋白酶B，L和D积累在AppNL-GF / NL-GF小鼠的淀粉样β斑块中，就像人类阿尔茨海默氏病患者中发生的那样。这些溶酶体蛋白的积累发生在神经病理学发展的早期，出现在观察到的最早和最小的淀粉样蛋白斑块中。AppNL-GF / NL-GF小鼠还表现出β-己糖胺酶和组织蛋白酶D / E的活性增强以及所选溶酶体网络蛋白（即LAMP1，组织蛋白酶D和微管相关蛋白轻链3（LC3-II））的升高水平。通过蛋白质印迹确定大脑皮层。组织蛋白酶D的升高并没有改变AppNL-GF / NL-GF小鼠中组织蛋白酶D与LAMP1之间的共定位程度。这些发现表明，溶酶体网络的扰动发生在AppNL-GF / NL-GF小鼠模型中，进一步证实了其在有症状的AD的动物模型中的使用。组织蛋白酶D的升高并没有改变AppNL-GF / NL-GF小鼠中组织蛋白酶D与LAMP1之间的共定位程度。这些发现表明，溶酶体网络的扰动发生在AppNL-GF / NL-GF小鼠模型中，进一步证实了其在有症状的AD的动物模型中的使用。组织蛋白酶D的升高并没有改变AppNL-GF / NL-GF小鼠中组织蛋白酶D与LAMP1之间的共定位程度。这些发现表明，溶酶体网络的扰动发生在AppNL-GF / NL-GF小鼠模型中，进一步证实了其在有症状的AD的动物模型中的使用。