H

AR-A014418 (41)

b-Secretase (BACE-1, b-site APP cleavage enzyme-1; Asp2; Memapsin) is a membrane-bound aspartyl proteinase. It is a zymogen, the activation of which requires the cleavage of its prodomain by a Furin-like proteinase. BACE-1 knockout mice develop normally and lack overt abnormal behaviors. Inhibitors of BACE-1 are drug targets to limit Ab formation without toxicity. The prototypic BACE-1 inhibitor is pepstatin 32. Newer BACE-1 inhibitors have potent activity against the isolated enzyme (IC50 = 1-400 nM) but limited cellular potency (IC50 ~ 1-50 mM).

g-Secretase is an apartyl protease catalyzing the intramembrane cleavage of APP together with b-secretase to produce the Ab40 and Ab42 peptides. The proteins linked to EOAD, the presenilins (mainly PS-1), constitute a complex with g-secretase together with the membrane proteins: nicastrin, Aph-1, and Pen-2. The challenge in finding inhibitors of g-secretase is that the enzyme has many substrates in addition to APP, some of which, e.g., Notch proteins, have a role in development.45 The g-secretase inhibitor, LY-450139 (33: Ki = 0.9 nM), inhibits Ab formation in cells, transgenic animals, and beagle dogs. LY-450139 (30 mg day_ 1 for 1 week followed by 40 mg day_ 1 for 5 weeks) decreased plasma levels of Ab40 ~ 40% in AD patients on stable doses of an AChE inhibitor. No differences in measures of cognition were observed, perhaps reflecting the need for longer trials in order to reveal added benefit of g-secretase inhibition.46

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