α- and β-secretase: Profound changes in Alzheimer's disease

Abstract

The amyloid plaque, a neuropathological hallmark of Alzheimer's disease, is produced by the deposition of β-amyloid (Aβ) peptide, which is cleaved from Amyloid Precursor Protein (APP) by the enzyme β-secretase. Only small amounts of Aβ form in normal brain; more typically this is precluded by the processing of APP by α-secretase. Here, we describe a decrease in α-secretase (81% of normal) and a large increase in β-secretase activity (185%) in sporadic Alzheimer's disease temporal cortex. Since α-secretase is present principally in neurons known to be vulnerable in Alzheimer's disease, and there is known competition between α- and β-secretase for the substrate APP, it is significant that the majority of Alzheimer samples tested here were low in α-secretase. Eighty percent of Alzheimer brains examined had an increase in β-secretase, a decrease in α-secretase, or both; which may account for the means by which the majority of people develop Alzheimer's disease. © 2002 Elsevier Science (USA). All rights reserved