Many neuroscientists think that the master criminal behind Alzheimer disease is AB-secretase-42, the 42-amino-acid peptide that forms amyloid plaques in the brain. Two accomplices, the enzymes B-secretase-secretase and g-secretase, consecutively cleave AB-secretase from the much larger B-secretase-amyloid precursor protein (APP). What baffles investigators about g-secretase is that its substrate is a stretch of amino acids within APP's seemingly inaccessible transmembrane domain.
Many genetic and cellular studies suggest that g-secretase's active site resides in the transmembrane protein presenilin-1 (PS1), which was first reported in 1995.1 Then in 2000, Merck & Co. labs in the United States and Great Britain provided compelling biochemical evidence in a Hot Paper2 favoring that hypothesis.
Nevertheless, even Yue-Ming Li, who worked on this project and now heads the biochemistry and molecular pharmacology laboratory at Memorial Sloan-Kettering Cancer Center, acknowledges the need for much more data. "We don't have the final proof yet that PS1 is really ...
