Paz Gavilán M, Vela José, Castaño Angélica, Ramos Blanca, del Río Juan C, Vitorica Javier, Ruano Diego
Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/ Profesor García González no. 2, 41012 Sevilla, Spain.
Neurobiol Aging. 2006 Jul;27(7):973-82. doi: 10.1016/j.neurobiolaging.2005.05.010. Epub 2005 Jun 17.
Aging represents the main risk factor to develop Alzheimer disease (AD) and protein aggregation constitutes a pathological hallmark thought to be involved in the etiology of this disease. Here, we show that, in basal conditions, the expression of chaperones calnexin, protein disulfide isomerase (PDI) and Grp78 was decreased in aged hippocampus, whereas the protein ubiquitination increased, suggesting the existence of age-related deficits in the systems involved in the defense against unfolded proteins. Interestingly, when cellular stress was induced by intra-hippocampal lactacystin injection, the aged rats were less efficient than young animals in alleviating the protein accumulation and, as an important factor, did not induce the expression of chaperones as young animals. However, the expression of the pro-apoptotic factor CHOP/GADD153 was induced and caspase-12 was activated in stressed aged rats but not in young animals. Current results demonstrated that unfolding protein response (UPR) is not correctly activated in aged rat hippocampus. Consequently, the up-regulation of apoptotic pathway mediators is increased in aged rats. Results might provide further understanding of the pathogenic mechanisms of age-related neurodegenerative disorders.
衰老代表了患阿尔茨海默病（AD）的主要风险因素，蛋白质聚集构成了一种病理特征，被认为与该疾病的病因有关。在此，我们表明，在基础条件下，伴侣蛋白钙连蛋白、蛋白质二硫键异构酶（PDI）和葡萄糖调节蛋白78（Grp78）在老年海马体中的表达降低，而蛋白质泛素化增加，这表明在抵御未折叠蛋白的系统中存在与年龄相关的缺陷。有趣的是，当通过海马内注射乳胞素诱导细胞应激时，老年大鼠在减轻蛋白质积累方面比年轻动物效率更低，并且作为一个重要因素，它们不像年轻动物那样诱导伴侣蛋白的表达。然而，促凋亡因子CHOP/GADD153的表达在应激的老年大鼠中被诱导，并且半胱天冬酶-12被激活，而在年轻动物中则没有。目前的结果表明，老年大鼠海马体中的未折叠蛋白反应（UPR）未被正确激活。因此，老年大鼠中凋亡途径介质的上调增加。这些结果可能为进一步理解与年龄相关的神经退行性疾病的致病机制提供帮助。
