Mutations in APP have independent effects on Abeta and CTFgamma generation.
Understanding the molecular mechanism of beta-amyloid (Abeta) 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 gamma-secretase cleavage at two topologically distinct sites: a site in the middle of the TM domain that is crucial for the generation of Abeta-peptides, and a site close to the cytoplasmic border (S3-like/epsilon site) of the TM domain that leads to production of the APP intracellular domain (CTFgamma/AICD). We demonstrate that, in contrast to the unique effect of familial Alzheimer's disease (FAD) mutations in APP on Abeta42 production, some but not all FAD mutations also affect CTFgamma generation. Furthermore, changes in total CTFgamma levels do not correlate with either an increase or a decrease of any Abeta species, and inhibition of Abeta-peptide formation starting from position +1 (Abeta1-x) does not affect CTFgamma production. These results suggest that cleavage at the gamma40/42- and the S3-like sites can be dissociated, and that APP signaling and Abeta production are not tightly linked.
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
Silva
S
Hecimovic
Jun
J
Wang
Georgia
G
Dolios
Maribel
M
Martinez
Rong
R
Wang
Alison M
AM
Goate
D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D010450:Endopeptidases / Q000737:chemistry; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000096:biosynthesis*; D021381:Protein Transport
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human