Pin-pointing APP Processing

Pin1 promotes isomerization of the phosphorylated APP cytoplasmic domain and non-amyloidogenic processing. The delivery of APP to endosomes for β-amyloid protein converting enzyme 1 (BACE1)–mediated processing proceeds by low-density lipoprotein-receptor-related protein (LRP1)-mediated endocytosis. For this to occur, APP is likely indirectly linked to LRP1 through Fe65 (acting as an adaptor) binding to the tail of APP in a phosphorylation-dependent manner. Pin1 also binds to the tail of APP, especially to the phosphorylated Thr⁶⁶⁸-Pro⁶⁶⁹ in cis conformation, and catalyzes conversion to the trans isomer that undergoes rapid dephosphorylation, thus promoting the non-amyloidogenic processing of APP. Enhanced Pin1 activity could also prevent endocytic delivery of APP to BACE1 by competing with the action of Fe65, an activity that may present a novel target to decrease amyloid production.