Presenilins, Processing of β-Amyloid Precursor Protein, and Notch Signaling

specific functions. Notch itself is a single-pass transTwo seemingly unrelated avenues of research, Alzheimembrane receptor with large extracellular and intracelmer’s disease and developmental cell fate specification, lular domains (Figure 1A). During receptor maturation, have intersected at the presenilin and Notch genes. ReNotch is cleaved in its extracellular domain by furin or a cent reports bolster the idea that presenilins have a role, furin-like convertase; the two resulting fragments remain indeed a critical role, in Notch signaling, specifically in associated and are thought to be the form of Notch that the proteolytic processing of Notch. binds ligand at the cell surface. Members of the DSL Presenilins and the b-Amyloid Precursor Protein (Delta/Serrate/LAG-2) family are ligands for the Notch The presenilins are proteins that contain multiple transreceptor, while members of the CSL family (CBF1/Supmembrane domains, that localize primarily to the endopressor of Hairless/LAG-1) are transcription factors that plasmic reticulum and Golgi apparatus, and whose prefunction downstream of Notch. cise function is unknown (for reviews see Selkoe, 1998; The first suggestion that presenilins are involved in Price et al., 1998). Human presenilin-1 and presenilin-2 the Notch pathway came with the finding in C. elegans were identified as the genes mutated in dominant familthat the presenilin gene sel-12 potentiates signaling by ial presenile (i.e., early onset) Alzheimer’s disease (AD) LIN-12 and GLP-1. Li and Greenwald (1997) and Westlinked to chromosomes 14 and 1, respectively. Mutalund et al. (1999) provide evidence that the second C. tions in the Caenorhabditis elegans presenilin gene selelegans presenilin gene hop-1 is genetically redundant 12 were identified as recessive suppressors of a gainwith sel-12. Li and Greenwald use the technique of RNAof-function allele of lin-12, one of the worm Notch genes. mediated interference to reduce hop-1 activity, while Mouse presenilins-1 and -2, another C. elegans preseniWestlund et al. isolated a hop-1 mutant. Both groups lin gene hop-1, and Drosophila melanogaster Presenilin find that reduction of the function of both sel-12 and were identified based on sequence similarity to the other hop-1 results in phenotypes not observed with the represenilins. C. elegans also has a third, divergent memduction of the function of either sel-12 or hop-1 alone ber of the presenilin family, spe-4, that is required during (summarized in Table 1). These phenotypes are similar spermatogenesis. to those seen with mutations in glp-1 and lin-12. With Mutations in the mammalian presenilin genes affect the isolation of a hop-1 mutant, further analysis of the the proteolytic processing of the b-amyloid precursor functions of sel-12 and hop-1 at the cellular level is now protein (APP), which is cleaved to produce the amyloid possible. b peptide (Ab), the principal component of the amyloid Struhl and Greenwald (1999) and Ye et al. (1999) report plaques found in the brains of all AD patients (Figure 1). the isolation of mutations in Drosophila Presenilin (variTo produce Ab, APP is first cleaved at an extracellular ously abbreviated DPS, Dps, PS, and Psn). Both groups site by the b-secretase activity, then at a site in the observe in their Presenilin mutants several phenotypes transmembrane domain by the g-secretase activity. The associated with reduced Notch function (Table 1). Thus, g-secretase cleavage can occur at one of two sites to in worms and flies loss of presenilin function results in produce either a 40–amino acid peptide (Ab40) or a phenotypes associated with reduced Notch function. 42–amino acid peptide (Ab42). The Ab42 peptide is more While presenilin-1 knockout mice exhibit defects in tislikely to aggregate in vitro and is the first species to sues also affected in Notch1 knockout mice, the phenoaccumulate as plaques in AD brains. Cultured cells and types are not identical (Table 1), possibly due to genetic mice expressing presenilin transgenes that carry the redundancy between presenilin-1 and presenilin-2. mutations found in familial AD display a subtle difference Altered Notch Proteolysis in presenilin Mutants in the processing of APP: though total Ab levels are not The expression level and subcellular localization of Notch significantly altered, more Ab42 is generated relative to are not drastically altered in neurons cultured from preAb40 in the mutants. This increased production of Ab42 senilin-1 knockout mice (De Strooper et al., 1999) or in may be the basis for the aggressive form of AD that Drosophila Presenilin mutants (Struhl and Greenwald, develops in individuals carrying such presenilin muta1999; Ye et al., 1999). Presenilin therefore appears to tions. Cells derived from presenilin-1 knockout mice, be required for the posttranslational regulation of Notch. in contrast, produce abnormally low levels of both Ab (The lower Notch1 and Deltalike1 levels observed in