To elucidate the roles of the APP intracellular domain (AICD) in the development of Alzheimer's disease, a yeast two-hybrid system was used to screen for AICD-interacting proteins. Our result revealed that FKBP12, an immunophilin with a peptidyl-prolyl cis-trans isomerase (PPIase) activity, may interact with AIM This interaction was confirmed by coinummoprecipitation studies. FKBP12 has been shown to be expressed at a higher level in areas of pathology of patients with neurodegenerative diseases. In addition, Pin1, a member of another PPIase family, has been suggested to be involved in the amyloidogenic APP processing and A beta production. The interaction between FKBP12 and AICD might hint at a possible role FKBP12 plays, probably in a fashion similar to Pin1, in the amyloidogenesis of APP. We also found that the interaction was interfered, in a dose-dependent manner, by FK506, whose neuroprotective effect has been suggested to be correlated with its PPIase inhibitory activity. (c) 2006 Elsevier Inc. All rights reserved.