Mutations in APP have independent effects on Aβ and CTFγ generation

Understanding the molecular mechanism of β-amyloid (Aβ) generation is crucial for Alzheimer''s disease pathogenesis as well as for normal APP function. The transmembrane domain (TM) of APP appears to undergo presenilin-dependent γ-secretase cleavage at two topologically distinct sites: a site in the middle of the TM domain that is crucial for the generation of Aβ-peptides, and a site close to the cytoplasmic border (S3-like/ɛ site) of the TM domain that leads to production of the APP intracellular domain (CTFγ/AICD). We demonstrate that, in contrast to the unique effect of familial Alzheimer''s disease (FAD) mutations in APP on Aβ42 production, some but not all FAD mutations also affect CTFγ generation. Furthermore, changes in total CTFγ levels do not correlate with either an increase or a decrease of any Aβ species, and inhibition of Aβ-peptide formation starting from position +1 (Aβ1–x) does not affect CTFγ production. These results suggest that cleavage at the γ40/42- and the S3-like sites can be dissociated, and that APP signaling and Aβ production are not tightly linked. [Copyright &y& Elsevier]