The invention provides methods and compositions relating to pen polypeptides having pen-specific structure and activity, related polynucleotides and modulators of pen function. The invention provides isolated pen hybridization probes and primers capable of specifically hybridizing with natural pen genes, pen-specific binding agents such as specific antibodies, and methods of making and using the subject compositions in diagnosis (e.g. genetic hybridization screens for pen transcripts), therapy (e.g. pen inhibitors to modulate APP processing) and in the biopharmaceutical industry (e.g. as immunogens, reagents for screening chemical libraries for lead pharmacological agents, etc.).