In the non-amyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by an a-secretase within the Ap sequence, thus precluding Ap peptide generation. Following a-secretase cleavage, the C-terminal APP fragment undergoes y-cleavage, leading to the generation of the p3 peptide, which is generally not found in the amyloid plaques characteristic for Alzheimer's disease (AD). The a-secretase cleavage releases the N-terminal ectodomain of APP (APPsa), which has neurotrophic and neuroprotective properties. Therefore, activation of the non-amyloidogenic pathway provides a logical alternative strategy to p- or y-secretase inhibition for treatment of AD. Although cleavage by a-secretase was the first proteolytic pathway of APP to be characterized in detail, this idea remained almost forgotten as long as the a-secretase had not been identified.
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