Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Curr Alzheimer Res. 2011 Sep;8(6):623-32. doi: 10.2174/156720511796717168.
Alzheimer disease (AD) is the most common cause of dementia in adults. Aberrant hyperphosphorylation of microtubule associated protein Tau and neurofilament-M/H is one of the pathological hallmarks of AD. Most of the therapeutic strategies for treating AD are based on the inhibition of protein kinases such as glycogen synthase kinase-3β, cyclin-dependent kinase 5, and other Tau kinases. Here, we focus on protein phosphatase 2A (PP2A) as a key player in AD. PP2A expression and activity are downregulated in AD brain, contributing to the aberrant phosphorylation of Tau and NF proteins in AD. Recent data published from our lab as well as others on PP2A deregulation in AD is reviewed. The role of peptidyl prolyl isomerase Pin1 in regulation of PP2A mediated neurodegeneration is further analyzed. Development of drugs for AD could be based on restoration of PP2A activity or targeting Pin1.
阿尔茨海默病（AD）是成年人中最常见的痴呆症病因。微管相关蛋白 Tau 和神经丝-M/H 的异常过度磷酸化是 AD 的病理标志之一。大多数治疗 AD 的策略都是基于抑制蛋白激酶，如糖原合酶激酶-3β、细胞周期蛋白依赖性激酶 5 和其他 Tau 激酶。在这里，我们将重点关注蛋白磷酸酶 2A（PP2A）作为 AD 的关键参与者。AD 大脑中的 PP2A 表达和活性下调，导致 Tau 和 NF 蛋白在 AD 中的异常磷酸化。我们实验室以及其他实验室最近发表的关于 AD 中 PP2A 失调的数据进行了综述。肽基脯氨酰顺反异构酶 Pin1 在调节 PP2A 介导的神经退行性变中的作用进一步进行了分析。基于恢复 PP2A 活性或靶向 Pin1 的药物可能被开发用于 AD。
