Is Presenilin-1 Really Guilty of Dismembering Alzheimer Protein?

Image: Courtesy of Yue-Ming Li  HOW PHOTOACTIVATION WORKS: When a benzophenone group is attached to a g-secretase inhibitor and exposed to light, the benzophenone's oxygen turns into a triplet biradical, which bonds covalently with a nearby protein. 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, consecutiv

Douglas Steinberg
Oct 27, 2002
Image: Courtesy of Yue-Ming Li
 HOW PHOTOACTIVATION WORKS: When a benzophenone group is attached to a g-secretase inhibitor and exposed to light, the benzophenone's oxygen turns into a triplet biradical, which bonds covalently with a nearby protein.

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...