New strategies for Alzheimer's disease and cognitive impairment

Abstract

Approximately five million people suffer with Alzheimer's disease (AD) and more than twenty-four million people are diagnosed with AD, pre-senile dementia, and other disorders of cognitive loss worldwide. Furthermore, the annual cost per patient with AD can approach $200,000 with an annual population aggregate cost of $100 billion. Yet, complete therapeutic prevention or reversal of neurovascular injury during AD and cognitive loss is not achievable despite the current understanding of the cellular pathways that modulate nervous system injury during these disorders. As a result, identification of novel therapeutic targets for the treatment of neurovascular injury would be extremely beneficial to reduce or eliminate disability from diseases that lead to cognitive loss or impairment. Here we describe the capacity of intrinsic cellular mechanisms for the novel pathways of erythropoietin and forkhead transcription factors that may offer not only new strategies for disorders such as AD and cognitive loss, but also function as biomarkers for disease onset and progression.

Figure 1

Erythropoietin (EPO) regulates the intracellular trafficking of the forkhead transcription factor FoxO3a in endothelial cells (ECs) during oxygen glucose deprivation (OGD). EPO (10 ng/ml) was administered to ECs 1 hour prior to exposure of OGD for an 8 hour period. Immunofluorescent staining for FoxO3a at 6 hours following OGD was performed with primary rabbit anti-FoxO3a antibody followed by Texas red conjugated antirabbit secondary antibody. Nuclei of ECs were counterstained with DAPI. Control cells were untreated and not exposed to OGD. In control cells, FoxO3a remains primarily in the cytoplasm of cells with the nuclei visible in merged images and indicated by the white arrows. In contrast, OGD activates FoxO3a to translocate to the nucleus demonstrating FoxO3a in the cytoplasm and nuclei of these cells in merged images. However, EPO prevents nuclear translocation of FoxO3a by retaining FoxO3a in the cytoplasm similar to control cells with nuclei visible in merged images and indicated by the white arrows.