Caballero Cristina, Jimenez Sebastian, Moreno-Gonzalez Ines, Baglietto-Vargas David, Sanchez-Varo Raquel, Gavilan M Paz, Ramos Blanca, Del Rio Juan Carlos, Vizuete Marisa, Gutierrez Antonia, Ruano Diego, Vitorica Javier
Departmento de Bioquimica, Bromatologia, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
J Neurosci Res. 2007 Mar;85(4):787-97. doi: 10.1002/jnr.21172.
The detection of the early phenotypic modifications of Alzheimer's disease (AD) models is fundamental to understand the progression and identify pharmacologic targets of this pathology. However, a large variability within different models and between age-matched mice from the same model has been observed. This variability could be due to heterogeneity in the Abeta production. Present results showed the existence of a large variability in the Abeta deposition in both hippocampus and cortex in 6-month-old PS1xAPP mice. This variability was not due to the expression of hAPP751SL, however, linear relationship between hPS1M146L mRNA and Abeta production was identified. The Abeta content was related to the incorporation of the hPS1M146L into functional gamma-secretase complexes, detected by the presence of the corresponding human or endogenous PS1-CTFs. Animals expressing low amount of hPS1M146L mRNA, displayed low hPS1-CTF incorporation and produced a low amount of Abeta peptides. Conversely, mice with relatively high hPS1 mRNA expression displayed high hPS1-CTF and high Abeta deposition. Furthermore, the Abeta total and Abeta1-42 content was increased dramatically by the expression of hPS1M146L (as compared with transgenic APPsl littermates). Therefore, variations in the expression of transgenic form of hPS1M146L in this model, or even between different models, influenced strongly the incorporation of the mutated PS1 into functional gamma-secretase complexes, the production of Abeta peptides and, in consequence, the detrimental effects of Abeta peptides. These data might implicate an "apparent gain-of-function" of the gamma-secretase complex by the expression of the mutated PS1M146L.
检测阿尔茨海默病（AD）模型的早期表型改变对于理解该疾病的进展以及确定其病理的药理学靶点至关重要。然而，在不同模型之间以及同一模型中年龄匹配的小鼠之间观察到了很大的变异性。这种变异性可能是由于β淀粉样蛋白（Aβ）产生的异质性所致。目前的结果表明，在6个月大的PS1xAPP小鼠的海马体和皮质中，Aβ沉积存在很大的变异性。然而，这种变异性并非由于hAPP751SL的表达，而是确定了hPS1M146L mRNA与Aβ产生之间的线性关系。Aβ含量与hPS1M146L掺入功能性γ-分泌酶复合物有关，这可通过相应的人或内源性PS1-CTFs的存在来检测。表达低水平hPS1M146L mRNA的动物，显示出低水平的hPS1-CTF掺入，并且产生少量的Aβ肽。相反，hPS1 mRNA表达相对较高的小鼠显示出高hPS1-CTF和高Aβ沉积。此外，hPS1M146L的表达使Aβ总量和Aβ1-42含量显著增加（与转基因APPsl同窝小鼠相比）。因此，该模型中hPS1M146L转基因形式表达的变化，甚至不同模型之间的变化，强烈影响了突变型PS1掺入功能性γ-分泌酶复合物、Aβ肽的产生，以及Aβ肽的有害作用。这些数据可能暗示了突变型PS1M146L的表达导致γ-分泌酶复合物出现“明显的功能获得性”。
