β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE

R Vassar, BD Bennett, S Babu-Khan, S Kahn… - science, 1999 - science.org
R Vassar, BD Bennett, S Babu-Khan, S Kahn, EA Mendiaz, P Denis, DB Teplow, S Ross…
science, 1999science.org
Cerebral deposition of amyloid β peptide (Aβ) is an early and critical feature of Alzheimer's
disease. Aβ generation depends on proteolytic cleavage of the amyloid precursor protein
(APP) by two unknown proteases: β-secretase and γ-secretase. These proteases are prime
therapeutic targets. A transmembrane aspartic protease with all the known characteristics of
β-secretase was cloned and characterized. Overexpression of this protease, termed BACE
(for beta-site APP-cleaving enzyme) increased the amount of β-secretase cleavage …
Cerebral deposition of amyloid β peptide (Aβ) is an early and critical feature of Alzheimer's disease. Aβ generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: β-secretase and γ-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of β-secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of β-secretase cleavage products, and these were cleaved exactly and only at known β-secretase positions. Antisense inhibition of endogenous BACE messenger RNA decreased the amount of β-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as β-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for β-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.
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