Independent inhibition of Alzheimer disease beta- and gamma-secretase cleavage by lowered cholesterol levels.

The major molecular risk factor for Alzheimer disease so far identified is the amyloidogenic peptide Abeta(42). In addition, growing evidence suggests a role of cholesterol in Alzheimer disease pathology and Abeta generation. However, the cellular mechanism of lipid-dependent Abeta production remains unclear. Here we describe that the two enzymatic activities responsible for Abeta production, beta-secretase and gamma-secretase, are inhibited in parallel by cholesterol reduction. Importantly, our data indicate that cholesterol depletion within the cellular context inhibits both secretases additively and independently from each other. This is unexpected because the beta-secretase beta-site amyloid precursor protein cleaving enzyme and the presenilin-containing gamma-secretase complex are structurally different from each other, and these enzymes are apparently located in different subcellular compartments. The parallel and additive inhibition has obvious consequences for therapeutic research and may indicate an intrinsic cross-talk between Alzheimer disease-related amyloid precursor protein processing, amyloid precursor protein function, and lipid biology.