RESUMEN
Alzheimer disease is characterized by the accumulation of ß-amyloid (Aß) plaques and tau-laden neurofibrillary tangles. Emerging studies suggest that in neurodegenerative diseases, aggregation of one protein species can promote other proteinopathies and that inflammation plays an important role in this process. To study the interplay between Aß deposition, tau pathology, and microgliosis, we established a new AD transgenic mouse model by crossing 5xfAD mice with Thy-Tau22 transgenic mice. The resulting 'T5x' mice exhibit a greater than three-fold increase in misfolded and hyperphosphorylated tau and further substantiates the hypothesis that Aß accelerates tau pathology. Surprisingly, T5x mice exhibit a 40-50 % reduction in Aß plaque load and insoluble Aß species when compared with aged-matched 5xfAD littermates. T5x mice exhibit significant changes in cytokine production, an almost doubling of microglial number, and a dramatic shift in microglia activation state. Furthermore, T5x microglia exhibit increased phagocytic capacity that enhances the clearance of insoluble Aß and decreasing plaque load. Therefore, our results suggest that strategies to increase the phagocytic ability of microglia can be employed to reduce Aß and that tau-induced changes in microglial activation state can promote the clearance of Aß.