An early role of amyloid-β peptide (Aβ) aggregation in Alzheimer's disease pathogenesis is well established. However, the contribution of intracellular or extracellular forms of Aβ to the neurodegenerative process is a subject of considerable debate. We here describe transgenic mice expressing Aβ1-40 (APP47) and Aβ1-42 (APP48) with a cleaved signal sequence to insert both peptides during synthesis into the endoplasmic reticulum. Although lower in transgene mRNA, APP48 mice reach a higher brain Aβ concentration. The reduced solubility and increased aggregation of Aβ1-42 may impair its degradation. APP48 mice develop intracellular Aβ lesions in dendrites and lysosomes. The hippocampal neuron number is reduced already at young age. The brain weight decreases during aging in conjunction with severe white matter atrophy. The mice show a motor impairment. Only very few Aβ1-40 lesions are found in APP47 mice. Neither APP47 nor APP48 nor the bigenic mice develop extracellular amyloid plaques. While intracellular membrane expression of Aβ1-42 in APP48 mice does not lead to the AD-typical lesions, Aβ aggregates develop within cells accompanied by considerable neurodegeneration.

中文翻译：

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神经元内 Aβ42 而非 Aβ40 的转基因表达会导致细胞 Aβ 病变、变性和功能障碍，但没有典型的阿尔茨海默病病理。

淀粉样蛋白-β 肽 (Aβ) 聚集在阿尔茨海默病发病机制中的早期作用已得到充分证实。然而，细胞内或细胞外形式的 Aβ 对神经退行性过程的贡献是一个颇有争议的话题。我们在此描述了表达 Aβ1-40 (APP47) 和 Aβ1-42 (APP48) 的转基因小鼠，其带有切割的信号序列，可在合成过程中将两种肽插入内质网。虽然转基因 mRNA 较低，但 APP48 小鼠的脑 Aβ 浓度较高。Aβ1-42 溶解度降低和聚集增加可能会损害其降解。APP48 小鼠在树突和溶酶体中发生细胞内 Aβ 损伤。海马神经元数量在年轻时就已经减少了。大脑重量随着年龄的增长而减少，同时伴有严重的白质萎缩。小鼠表现出运动障碍。在 APP47 小鼠中仅发现很少的 Aβ1-40 病变。APP47 和 APP48 以及生物小鼠都不会产生细胞外淀粉样蛋白斑块。虽然 APP48 小鼠中 Aβ1-42 的细胞内膜表达不会导致 AD 典型病变，但 Aβ 聚集体在细胞内发展并伴有相当大的神经变性。