Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE

R Vassar; B D Bennett; S Babu-Khan; S Kahn; E A Mendiaz; P Denis; D B Teplow; S Ross; P Amarante; R Loeloff; Y Luo; S Fisher; J Fuller; S Edenson; J Lile; M A Jarosinski; A L Biere; E Curran; T Burgess; J C Louis; F Collins; J Treanor; G Rogers; M Citron

doi:10.1126/science.286.5440.735

Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE

Science. 1999 Oct 22;286(5440):735-41. doi: 10.1126/science.286.5440.735.

Authors

Affiliation

¹ Amgen, Inc., One Amgen Center Drive, M/S 29-2-B, Thousand Oaks, CA 91320-1799, USA.

PMID: 10531052
DOI: 10.1126/science.286.5440.735

Abstract

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.

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / enzymology*
Amino Acid Motifs
Amino Acid Sequence
Amyloid Precursor Protein Secretases
Amyloid beta-Peptides / biosynthesis*
Amyloid beta-Protein Precursor / metabolism*
Animals
Aspartic Acid Endopeptidases / chemistry
Aspartic Acid Endopeptidases / genetics
Aspartic Acid Endopeptidases / isolation & purification*
Aspartic Acid Endopeptidases / metabolism*
Binding Sites
Brain / enzymology
Brain / metabolism
Cell Line
Cloning, Molecular
Endopeptidases
Endosomes / enzymology
Gene Expression
Gene Library
Golgi Apparatus / enzymology
Humans
Hydrogen-Ion Concentration
Molecular Sequence Data
Oligonucleotides, Antisense / pharmacology
Peptides / metabolism
Protease Inhibitors / pharmacology
RNA, Messenger / genetics
RNA, Messenger / metabolism
Recombinant Fusion Proteins / metabolism
Transfection

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Oligonucleotides, Antisense
Peptides
Protease Inhibitors
RNA, Messenger
Recombinant Fusion Proteins
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
BACE1 protein, human

Associated data

GENBANK/AF190725
GENBANK/AF190726
GENBANK/AF190727