Zwei neuartige Aspartylproteasen BACE-1 und BACE-2: Charakterisierung und Vergleich der katalytischen Spezifitäten bei der Proteolyse des Alzheimer beta-Amyloid Vorläufer Proteins

b-Site amyloid precursor protein cleavage enzyme (BACE)-1and BACE-2 are members of a novel family of membrane-bound aspartyl proteases. While BACE-1 is known to cleaveb-amyloid precursor protein (bAPP) at the b-secretase siteand to be required for the generation of amyloid b-peptide(Ab), the role of its homologue BACE-2 in amyloidogenesis isless clear. We now demonstrate that BACE-1 and BACE-2have distinct specificities in cleavage of bAPP in culturedcells. Radiosequencing of the membrane-bound C-terminalcleavage product revealed that BACE-2 cleaves bAPP in themiddle of the Ab domain between phenylalanines 19 and 20,resulting in increased secretion of APPs-aand p3-like prod-ucts and reduced production of Ab species. This cleavage canoccur in the Golgi and later secretory compartments. We alsodemonstrate that BACE-1-mediated cleavage of bAPP atAsp1 of the Ab domain can occur as early as in the endo-plasmic reticulum, while cleavage at Glu11 occurs in latercompartments. These data indicate that the distinct specifici-ties of BACE-1 and BACE-2 in their cleavage of bAPP dif-ferentially affect the generation of Ab.