P1–388: Failure of cytoplasmic–nuclear transport in Alzheimer's disease

Many proteins including various cyclins and cyclin–dependent kinases together with their cognate inhibitors have been reported to be ectopically localized in the cytoplasm rather than the nucleus in the vulnerable neurons in Alzheimer's Disease (AD). Since nuclear localization is critical to function and the cytoplasmic–nuclear transportation of large molecules, such as proteins, is actively regulated, the aberrant localization of nuclear proteins to the cytoplasm in AD could be caused by the failure of the cytoplasmic–nuclear transportation machinery and lead to deleterious consequences. We sought to investigate the alteration of cytoplasmic–nuclear transportation in the pathogenesis of AD. The level of importin α is determined in AD and normal control by immunohistochemistry. The effect of oxidative stress on the localization of importin α is studied using SHSY5Y cells. In an effort to determine the cytoplasmic–nuclear transportation in the vulnerable neurons in AD, we analyzed the localization of importin α, an important component of cytoplasmic–nuclear transportation, in the hippocampal neurons in AD and age–matched control patients by immunocytochemistry. We found that importin α is accumulated in Hirano bodies in AD, one of the major pathological markers of disease, in contrast to the normal diffuse cytoplasmic localization in control patients. These data suggest a hindrance in the proper transport of importin α between the cytoplasm and nucleus in AD. Importantly, importin α was not detected in neurofibrillary tangles (NFT) in AD and Lewy body in Parkinson's disease (PD) suggesting that the accumulation of importin α in the Hirano body is a specific event, rather than a general characteristic of inclusion bodies found in different neurodegenerative diseases. Moreover, we found that oxidative stress, an early contributor to the pathogenesis of AD, induces the accumulations importin α in the nucleus and blocks shuttling of importin α in a cell culture model. Taken together, our results suggest the defects in importin–mediated cytoplasmic–nuclear transportation play a key role in the sequelae of pathogenic events in AD and that such events may be triggered by oxidative stress. Work in the authors' laboratories is supported by the Alzheimer Association, NIH and Phillip Morris USA.