Processing of beta-secretase by furin and other members of the proprotein convertase family

The amyloid plaques in brain of Alzheimer's disease patients. This peptide is generated from the amyloid precursor protein by two consecutive cleavage s. Cleavage at the N terminus is performed by the recently discovered beta -secretase (Bace). This aspartyl protease contains a propeptide that has to be removed to obtain mature Bace. Furin and other members of the furin fam ily of prohormone convertases are involved in this process. Surprisingly, b eta -secretase activity, neither at the classical Asp(1) position nor at th e Glu(11) position of amyloid precursor protein, seems to be controlled by this maturation step. Furthermore, we show that Glu(11) cleavage is a funct ion of the expression level of Bace, that it depends on the membrane anchor age of Bace, and that Asp(1) cleavage can be followed by Glu(11) cleavage. Our data suggest that pro-Bace could be active as a beta -secretase in the early biosynthetic compartments of the cell and could be involved in the ge neration of the intracellular pool of the amyloid peptide. We conclude that modulation of the conversion of pro-Bace to mature Bace is not a relevant drug target to treat Alzheimer's disease.