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Scheme 3.5.2. General hydrolysis by aspartic proteases.

other. The observed loss of neurons is accompanied by the formation of plaques consisting of amyloid b-peptide (Ab). A rational approach to a successful, causal therapy is based on a detailed understanding of Ab formation, deposition and the inflammatory consequences. Decisive functions were assigned to the amyloid precursor protein (APP) and its degrading aspartic proteases b-secretase (also called b-amyloid-converting enzyme: BACE) and the presenilins. Presenilin is sometimes called y-secretase, although there is a significant difference - presenilin is a mandatory component of y-secretase activity, but it serves also as a functional domain for other proteins such as Notch. This is very important, because the Notch protein complex regulates cell differentiation at the embryonic stage and has functions in adult tissue.

The C-terminal transmembrane domain of b-secretase is not strictly required for activity, but location of enzyme and substrate in the same membrane enhances kinetics and specificity.

Only after subsequent proteolysis by the innermembrane protease, y-secretase, between Val711 and Ile712 or Ala713 and Thr714 is the Ab protein finally released, 40 or 42 amino acids long, resulting in Ab40 and Ab42 and the C-terminal fragment C99. Despite being the minor cleavage product, Ab42 is the dominant factor in Ab deposition and plaque formation, serving as a deposition nucleus. Ab formation, deposition, and clearance are, therefore, highly attractive targets for drug develop-

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