gamma-Secretase: characterization and implication for Alzheimer disease therapy.
gamma-Secretase is a membrane-bound protease that cleaves within the transmembrane region of amyloid precursor protein to generate the C-termini of the Abeta peptides which are believed to play a central role in the neuropathology of Alzheimer's disease. An in vitro gamma-secretase assay using a recombinant substrate C100Flag has been developed to facilitate the characterization and identification of this enigmatic protease. Biochemical studies establish that gamma-secretase activity is catalyzed by a PS1-containing macromolecular complex. Moreover, the fact that the photoreactive active gamma-secretase inhibitor directed to the active site labels PS1 suggests that PS1 contains the active site of the protease. Presenilin/gamma-secretase as a potential target for AD therapy and its role in regulated intramembrane proteolysis are discussed.
Xu
Min
M
Department of Biological Chemistry, Merck Research Laboratories,WP16-206, West Point, PA 19486, USA.
Lai
Ming-Tain
MT
Huang
Qian
Q
DiMuzio-Mower
Jillian
J
Castro
José L
JL
Harrison
Timothy
T
Nadin
Alan
A
Neduvelil
Joseph G
JG
Shearman
Mark S
MS
Shafer
Jules A
JA
Gardell
Stephen J
SJ
Li
Yue-Ming
YM
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002219:Carbamates / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases / Q000032:analysis / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques / Q000379:methods*; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000378:metabolism*; D053764:Presenilin-1; D053766:Presenilin-2; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D002219:Carbamates; D004151:Dipeptides; D004791:Enzyme Inhibitors; C410009:L 685458; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human