The Presenilin/γ-Secretase Complex Regulates Production of Transcriptional Factors: Effects of FAD Mutations

First described for its b-amyloid-producing function, the presenilin (PS)-dependent g-secretase complex has since been shown to catalyze the e-cleavage of type I transmembrane cell surface proteins producing soluble peptides containing the intracellular domains (ICDs) of the cleaved proteins. These peptides act as regulators of gene expression, suggesting that the PS/g-secretase processing of cell-surface proteins is a key factor in surface-to-nucleus signal transduction and communication. Signal-induced gene expression mediates neuronal responses to environmental changes, and is a key event in neuronal survival and synaptic function. Many of the cell-surface proteins cleaved by the PS/g-secretase system are cell-surface receptors involved in diverse functions ranging from development and differentiation to cellcell adhesion and communication. Thus, the cleavage controlled by the PS/g-secretase system may be used to transmit information to the interior of the cell, including the nucleus, about specific changes taking place in the extracellular environment. Familial Alzheimer's disease (FAD) mutations may interfere with this flow of information by inhibiting the e-cleavage of cell-surface proteins and thus down-regulating production of biologically active ICDs. Here, we discuss how the study of the genetic and molecular aspects of Alzheimer's disease (AD) reveals a dual role for the PS/g-secretase complex in transcriptional regulation and in AD pathogenesis.