Secretases are enzymes that process APP into nonamyloidogenic and amyloidogenic fragments and exist in three subtypes: a, b, and g. Cleavage of APP by a-secretase followed by g-secretase produces peptide fragments in the nonamyloidogenic pathway, whereas cleavage by b-secretase followed by g-secretase produces the Ab peptide fragments that aggregate and deposit as plaques (Figure 3). Thus, both b- and g-secretases are potential targets for AD therapy, although g-secretases have shown toxic liabilities. Two zinc-dependent metalloproteinases, ADAM10 and ADAM 17 (TACE), are candidate genes for a-secretase. Since the latter enzyme produces cleavage products with neurotrophic properties, inhibition of this enzyme may be counterproductive.
Domains: Extracellular Transmembrane Intracellular
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