One of the hallmarks of AD pathology is the presence of neuritic plaques in the brains of afflicted individuals. These plaques are composed of intracellular and extracellular deposits of amyloid beta peptide (Abeta) surrounded by dystrophic neurites, reactive astrocytes, and microglia. The process of protein folding and mis-folding in AD pathology has gained significant attention in recent years with the discoveries that defects in folding and/or clearance of misfolded proteins can lead to insoluble protein plaques in the brain. Clearly, strategies aimed to reduce the rate of oligomerization of Abeta oligomers or decrease the amount of Abeta fibrils are important therapeutic directions for the clinical treatment of AD. We have been studying small molecule orally-available compounds, called immunophilin ligands, that bind to a class of proteins called PPIases which in turn regulate APP processing and Abeta production. The overall goals of this ADDF application is to provide preclinical proof of concept that immunophilin ligands can decrease Abeta burden in animal models of AD.