da Cruz e Silva Edgar F, da Cruz e Silva Odete A B
Centro de Biologia Celular, Universidade de Aveiro, Aveiro, Portugal.
Neurochem Res. 2003 Oct;28(10):1553-61. doi: 10.1023/a:1025630627319.
Numerous lines of evidence place signal transduction cascades at the core of many processes having a direct role in neurodegeneration and associated disorders. Key players include neurotransmitters, growth factors, cytokines, hormones, and even binding and targeting proteins. Indeed, abnormal phosphorylation of key control proteins has been detected in many cases and is thought to underlie the associated cellular dysfunctions. Several signaling cascades have been implicated, affecting processes as varied as protein processing, protein expression, and subcellular protein localization, among others. The Alzheimer's amyloid precursor protein (APP) is a phosphoprotein, with well-defined phosphorylation sites but whose function is not clearly understood. The factors and pathways regulating the processing of APP have been particularly elusive, both in normal ageing and the Alzheimer's disease (AD) condition. Not surprisingly, the physiological function(s) of the protein remain(s) to be elucidated, although many hypotheses have been advanced. Nonetheless, considerable data has accumulated over the last decade, placing APP in key positions to be modulated both directly and indirectly by phosphorylation and phosphorylation-dependent events. The pathological end product of APP processing is the main proteinaceous component of the hallmark senile plaques found in the brains of AD patients, that is, a toxic peptide termed Abeta. In this minireview we address the importance of phosphorylation and signal transduction cascades in relation to APP processing and Abeta production. The possible use of the identified molecular alterations as therapeutic targets is also addressed.
大量证据表明，信号转导级联反应在许多直接参与神经退行性变及相关疾病的过程中处于核心地位。关键参与者包括神经递质、生长因子、细胞因子、激素，甚至还有结合蛋白和靶向蛋白。事实上，在许多情况下都检测到关键调控蛋白的异常磷酸化，并且认为这是相关细胞功能障碍的基础。已涉及多种信号级联反应，影响蛋白质加工、蛋白质表达和亚细胞蛋白质定位等多种过程。阿尔茨海默病淀粉样前体蛋白（APP）是一种磷蛋白，具有明确的磷酸化位点，但其功能尚不清楚。在正常衰老和阿尔茨海默病（AD）情况下，调节APP加工的因素和途径一直特别难以捉摸。毫不奇怪，尽管提出了许多假说，但该蛋白的生理功能仍有待阐明。尽管如此，在过去十年中已经积累了大量数据，使APP处于可通过磷酸化和磷酸化依赖性事件直接和间接调节的关键位置。APP加工的病理终产物是AD患者大脑中标志性老年斑的主要蛋白质成分，即一种名为β淀粉样蛋白的毒性肽。在本综述中，我们阐述了磷酸化和信号转导级联反应与APP加工及β淀粉样蛋白产生的关系。还讨论了将已确定的分子改变用作治疗靶点的可能性。
