Dickey Chad, Kraft Clara, Jinwal Umesh, Koren John, Johnson Amelia, Anderson Laura, Lebson Lori, Lee Daniel, Dickson Dennis, de Silva Rohan, Binder Lester I, Morgan David, Lewis Jada
Department of Molecular Pharmacology and Physiology, Johnnie B. Byrd Sr. Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, USA.
Am J Pathol. 2009 Jan;174(1):228-38. doi: 10.2353/ajpath.2009.080764. Epub 2008 Dec 12.
We have extensively analyzed the biochemical and histochemical profiles of the tau protein from the rTg4510 transgenic mouse model in which the animals uniquely develop forebrain tau pathologies similar to those found in human tauopathies. Levels of several soluble phosphorylated tau species were highest at 1 month relative to later time points, suggesting that certain tau hyperphosphorylation events were insufficient to drive tangle formation in young mice. Despite a robust, pre-tangle-like accumulation of phospho-tau in 1-month-old mice, this material was cleared by 3 months, indicating that the young mouse brain either fails to facilitate tau insolubility or possesses an enhanced ability to clear tau relative to the adult. We also found that while heat shock protein expression increased with normal aging, this process was accelerated in rTg4510 mice. Moreover, by exploiting an exon 10 (-) specific antibody, we demonstrated that endogenous mouse tau turnover was slowed in response to human tau over-expression, and that this endogenous tau adopted disease-related properties. These data suggest that a younger brain fails to develop lasting tau pathology despite elevated levels of phosphorylated tau, perhaps because of reduced expression of stress-related proteins. Moreover, we show that the active production of small amounts of abnormal tau protein facilitates dysfunction and accumulation of otherwise normal tau, a significant implication for the pathogenesis of patients with Alzheimer's disease.
我们广泛分析了rTg4510转基因小鼠模型中tau蛋白的生化和组织化学特征，在该模型中，动物独特地发展出与人类tau蛋白病中发现的类似的前脑tau蛋白病变。相对于后期时间点，几种可溶性磷酸化tau蛋白的水平在1个月时最高，这表明某些tau蛋白过度磷酸化事件不足以驱动幼鼠中神经缠结的形成。尽管在1个月大的小鼠中磷酸化tau蛋白有强烈的、类似缠结前的积累，但这种物质在3个月时被清除，这表明幼鼠大脑要么无法促进tau蛋白的不溶性，要么相对于成年鼠具有更强的清除tau蛋白的能力。我们还发现，虽然热休克蛋白表达随正常衰老而增加，但在rTg4510小鼠中这一过程加速。此外，通过利用外显子10（-）特异性抗体，我们证明内源性小鼠tau蛋白的更新在人类tau蛋白过表达时减慢，并且这种内源性tau蛋白具有与疾病相关的特性。这些数据表明，尽管磷酸化tau蛋白水平升高，但较年轻的大脑无法发展出持久的tau蛋白病变，这可能是因为应激相关蛋白的表达减少。此外，我们表明少量异常tau蛋白的活性产生促进了正常tau蛋白的功能障碍和积累，这对阿尔茨海默病患者的发病机制具有重要意义。
