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PMID:10531052

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Citation

Vassar, R, Bennett, BD, Babu-Khan, S, Kahn, S, Mendiaz, EA, Denis, P, Teplow, DB, Ross, S, Amarante, P, Loeloff, R, Luo, Y, Fisher, S, Fuller, J, Edenson, S, Lile, J, Jarosinski, MA, Biere, AL, Curran, E, Burgess, T, Louis, JC, Collins, F, Treanor, J, Rogers, G and Citron, M (1999) Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735-41

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.

Links

PubMed

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BACE1

involved_in

GO:0016485: protein processing

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P05067)

Seeded From UniProt

complete

HUMAN:BACE1

enables

GO:0004190: aspartic-type endopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P05067)

Seeded From UniProt

complete

HUMAN:BACE1

located_in

GO:0016021: integral component of membrane

ECO:0000303: author statement without traceable support used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BACE1

located_in

GO:0005768: endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BACE1

located_in

GO:0005794: Golgi apparatus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:BACE1

located_in

GO:0005768: endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:BACE1

located_in

GO:0005794: Golgi apparatus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BACE1

involved_in

GO:0006508: proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BACE1

part_of

GO:0016021: integral component of membrane

ECO:0000303: author statement without traceable support used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BACE1

enables

GO:0004190: aspartic-type endopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BACE1

part_of

GO:0005768: endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BACE1

part_of

GO:0005794: Golgi apparatus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:BACE1

part_of

GO:0005768: endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:BACE1

part_of

GO:0005794: Golgi apparatus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:BACE1

enables

GO:0008233: peptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:BACE1

involved_in

GO:0050435: amyloid-beta metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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