title: Independent inhibition of Alzheimer disease beta- and gamma-secretase cleavage by lowered cholesterol levels.
abstract: 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.
authors.affiliation: Department of Neurology, Saarland University, Kirrbergerstrasse, 66421 Homburg/Saar, Germany.
authors.forename: Marcus O W
authors.initials: MO
authors.lastname: Grimm
authors.forename: Heike S
authors.initials: HS
authors.lastname: Grimm
authors.forename: Inge
authors.initials: I
authors.lastname: Tomic
authors.forename: Konrad
authors.initials: K
authors.lastname: Beyreuther
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
authors.forename: Christine
authors.initials: C
authors.lastname: Bergmann
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases