. "MODEL_NOTES=Panther Pathway: P00004 The presenilin gamma-secretase complex (consisting of presenilin, nicastrin, Aph-1 and Pen-2) has been demonstrated to cleave several single-transmembrane proteins within the membrane domain, including the amyloid precursor protein, Notch, ErbB4, E-cadherin, Nectin-1alpha, and CD44. This cleavage only occurs sequentially after an inital cleavage on the extracellular side of the transmembrane domain by an alternate enzyme. Cleavage of APP by gamma-secretase after beta-secretase cleavage yields Abeta, the backbone of senile plaques in Alzheimer's disease, and an intracellular fragment capable of nuclear translocation and subsequent effects on gene transcription. Similarly, presenilin-mediated cleavage of Notch and ErbB4 yield intracellular fragments capable of signal transduction. Medline=12142279 Medline=12834808 Medline=14598312 PMID: 12142279 PMID: 12834808 PMID: 14598312"^^ . . "Alzheimer disease-presenilin pathway"^^ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . "Alzheimer disease-presenilin pathway"^^ .