␤-Secretase (BACE) is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid ␤-peptide. Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. Phosphorylation/dephosphorylation affects the subcellular localization of BACE. BACE wild type and an S498D mutant that mimics phosphorylated BACE are predominantly located within juxtanuclear Golgi compartments and endosomes, whereas nonphosphorylatable BACE S498A accumulates in peripheral EEA1-positive endosomes. Antibody uptake assays revealed that reinternalization of BACE from the cell surface is independent of its phosphorylation state. After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes. Our results therefore demonstrate regulated trafficking of BACE within the secretory and endocytic pathway.

Di¡erences in social relationships among community members are often explained by di¡erences in genetic relationships. The current techniques of DNA analysis allow explicit testing of such a hypothesis. Here, we have analysed the genetic relationships for a community of wild bonobos (Pan paniscus) using nuclear and mitochondrial DNA markers extracted from faecal samples. Bonobos show an opportunistic and promiscuous mating behaviour, even with mates from outside the community. Nonetheless, we ¢nd that most infants were sired by resident males and that two dominant males together attained the highest paternity success. Intriguingly, the latter males are the sons of high-ranking females, suggesting an important in£uence of mothers on the paternity success of their sons. The molecular data support previous inferences on female dispersal and male philopatry. We ¢nd a total of ¢ve di¡erent mitochondrial haplotypes among 15 adult females, suggesting a frequent migration of females. Moreover, for most adult and subadult males in the group we ¢nd a matching mother, while this is not the case for most females, indicating that these leave the community during adolescence. Our study demonstrates that faecal samples can be a useful source for the determination of kinship in a whole community.

b-Site amyloid precursor protein cleavage enzyme (BACE)-1 and BACE-2 are members of a novel family of membranebound aspartyl proteases. While BACE-1 is known to cleave b-amyloid precursor protein (bAPP) at the b-secretase site and to be required for the generation of amyloid b-peptide (Ab), the role of its homologue BACE-2 in amyloidogenesis is less clear. We now demonstrate that BACE-1 and BACE-2 have distinct specificities in cleavage of bAPP in cultured cells. Radiosequencing of the membrane-bound C-terminal cleavage product revealed that BACE-2 cleaves bAPP in the middle of the Ab domain between phenylalanines 19 and 20, resulting in increased secretion of APPs-a-and p3-like products and reduced production of Ab species. This cleavage can occur in the Golgi and later secretory compartments. We also demonstrate that BACE-1-mediated cleavage of bAPP at Asp1 of the Ab domain can occur as early as in the endoplasmic reticulum, while cleavage at Glu11 occurs in later compartments. These data indicate that the distinct specificities of BACE-1 and BACE-2 in their cleavage of bAPP differentially affect the generation of Ab. Keywords: Alzheimer's disease, b-amyloid precursor protein, b-secretase, b-site amyloid precursor protein cleaving enzyme.

The ␤-amyloid precursor protein (␤APP) is one of the rare proteins known to be phosphorylated within its ectodomain. We have shown previously that ␤APP can be phosphorylated within secretory vesicles and at the cell surface (

The NAD + -dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) is a catabolic enzyme that controls the biological activities of prostaglandins by converting them into inactive keto-metabolites. Here we report the genomic organisation of the complete human PGDH gene and characterise its transcriptional regulation. The PGDH gene spans about 31 kb on chromosome 4 and contains 7 exons. Within 2·4 kb of the 5′-flanking sequence we identified two regions with clustered putative transcription factor binding sites. The distal promoter element PGDH-DE (positions−2152/−1944 relative to the start codon) contains binding sites for Ets and activating protein-1 (AP-1) flanked by two cAMP-responsive element-binding protein binding sites (CREB1, CREB2), whereas the proximal element PGDH-PE (−235/−153) includes an Ets and an AP-1 binding sequence. By electrophoretic mobility shift assay, no high affinity binding of Ets or AP-1 factors was observed with PGDH-PE, whereas we confirmed interaction of members of the Ets, AP-1 and CREB families of transcription factors with PGDH-DE. Transcriptional control of the PGDH promoter was assessed by transiently transfecting JEG-3 choriocarcinoma cells. A luciferase reporter gene construct containing the PGDH-PE was not induced by c-jun/c-fos in the absence or presence of co-expressed Ets-1. A construct carrying the PGDH-DE in front of the minimal homologous promoter was activated by co-transfection of expression vectors for AP-1 proteins. Mutation of the AP-1 or CREB2 site reduced the response to c-jun/c-fos, whereas mutation of the Ets site of the distal element reduced basal promoter activity. CREB activated the PGDH-DE construct through the CREB1 site. These results defined the distal element as an integrator of transcriptional regulation by AP-1, Ets and CREB proteins.