(From Abstract) Molecular genetic studies of familial Alzheimer's disease (FAD) have led to the identification of three genes which, when mutated can cause Alzheimer's disease (AD); beta-amyloid precursor protein (APP) and two related genes presenilin 1 (PS1) and presenilin 2 (PS2). The normal function of each of these molecules remains unknown, however, FAD mutations in all three genes result in an increase in levels of Ab42, an amyloidogenic fragment derived from APP by proteolytic processing. The dominant inheritance of the FAD phenotype suggests that these mutations either cause a gain of function or a loss of function via a dominant negative mechanism. PS1 knock-out mice are not viable and show multiple developmental abnormalities. Neurons derived from PS1 knock-out mice show a decrease in Ab levels suggesting that PS1 is required for normal APP processing and that the FAD mutations are not loss of function alleles. Genetic experiments have demonstrated that two presenilin homologs exist in C. elegans: sel-12 and hop-1, and that these molecules undergo similar endoproteolytic processing to their mammalian counterparts. Mutations that reduce sel-12 activity or sel-12 and hop-1 activity cause phenotypes that are consistent with a reduction in signaling through the lin-12 and glp-12 (Notch homologs) pathways. The phenotype of constitutively active lin-12 mutants lacking the extracellular and transmembrane domains are not modified by reduction of sel-12 activity suggesting that the sel-12 affects Notch signaling upstream of Notch activation. PS are membrane proteins with multiple membrane spanning domains that are primarily located within the endoplasmic reticulum. To determine the normal function of PS1 we will examine Notch maturation and processing in the presence and absence of functional PS1. We will extend our observations to the effect of PS function on APP maturation and processing and finally we will examine the effect of FAD mutations on the normal function of PS1 with respect to both Notch and APP. Specifically, we hypothesize that loss of PS function leads to reduced Notch signaling and reduced Ab because PS is required for normal Notch and APP maturation within the secretory pathway. We also hypothesize that FAD-causing mutations modify the normal activity of PS1 and that this change will have no effect on Notch signaling but will subtly alter APP processing. Through these studies we hope to determine the normal function of PS1 and to gain a better understanding of the role of PS1 in AD pathogenesis. We also anticipate that these studies will increase our understanding of the Notch signaling, a process that is important not only for many developmental decisions but for cancer as well.
