cleavage sites of alpha, beta, and gamma secretase enzymes, which suggests they might be involved in the onset of AD through altering the proteolysis of the Abeta peptide.13,14 N-terminal mutations in the Abeta sequence can affect the endosomal/lysosomal cleavage of Abeta, and might alter the beta secretase cleavages.12,15 Mutations near the cleavage site of alpha secretase (Glu693Lys, Glu693Gly, Glu693del, Asp694Asn) might change the processing of APP, in enhancing the proteolytic resistance of Abeta peptide.16,17 De Jonghe et al studied the APP mutations near the gamma secretase cleavage site.13 Missense mutations at codon 714-715 of APP decreased the secretion of Abeta 40, and the mutations at codon 716-717 increased the production and secretion of Abeta 42. This study suggests that gamma secretase cleavage might increase the ratio of Abeta 42 to Abeta 40.10–13,18
