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

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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