Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
Cerebral deposition of amyloid beta peptide (Abeta) is an early and critical feature of Alzheimer's disease. Abeta generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: beta-secretase and gamma-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of beta-secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were cleaved exactly and only at known beta-secretase positions. Antisense inhibition of endogenous BACE messenger RNA decreased the amount of beta-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as beta-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for beta-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.
Vassar
R
R
Amgen, Inc., One Amgen Center Drive, M/S 29-2-B, Thousand Oaks, CA 91320-1799, USA.
Bennett
B D
BD
Babu-Khan
S
S
Kahn
S
S
Mendiaz
E A
EA
Denis
P
P
Teplow
D B
DB
Ross
S
S
Amarante
P
P
Loeloff
R
R
Luo
Y
Y
Fisher
S
S
Fuller
J
J
Edenson
S
S
Lile
J
J
Jarosinski
M A
MA
Biere
A L
AL
Curran
E
E
Burgess
T
T
Louis
J C
JC
Collins
F
F
Treanor
J
J
Rogers
G
G
Citron
M
M
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D010450:Endopeptidases; D011992:Endosomes / Q000201:enzymology; D015870:Gene Expression; D015723:Gene Library; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016376:Oligonucleotides, Antisense; D010455:Peptides; D011480:Protease Inhibitors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human