Accumulation of the amyloid-b (Ab) plaque in the cerebral cortex is a critical event in the pathogenesis Alzheimer′s disease. Ab peptide is generated by proteolytic cleavage of the b-amyloid protein precursor(APP) at b- and g-sites by two proteases. APP is first cleaved by b-secretase, producing a soluble derivative of the protein and a membrane anchored 99-amino acid carboxy-terminal fragment (C99). The C99 fragment serves as substrate for g-secretase to generate the 4 kDa amyloid-b peptide, which is deposited in the brains of all sufferers of Alzheimer′s disease. The long-sought b-secretase was recently identified by several ...
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