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

Cerebral deposition of amyloid beta peptide (A beta) is an early and critic al feature of Alzheimer's disease. A beta 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 t argets. A transmembrane aspartic protease with all the known characteristic s of beta-secretase was cloned and characterized. Overexpression of this pr otease, termed BACE (for beta-site APP-cleaving enzyme) increased the amoun t of beta-secretase cleavage products, and these were cleaved exactly and o nly at known beta-secretase positions. Antisense inhibition of endogenous B ACE messenger RNA decreased the amount of beta-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same seq uence specificity as beta-secretase. Finally, the expression pattern and su bcellular Localization of BACE were consistent with that expected for beta- secretase. Future development of BACE inhibitors may prove beneficial for t he treatment of Alzheimer's disease.