Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability.
Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect gamma-secretase cleavage causing an increased relative ratio of Abeta42 to Abeta40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.
De Jonghe
C
C
Laboratory of Neurogenetics, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium.
Esselens
C
C
Kumar-Singh
S
S
Craessaerts
K
K
Serneels
S
S
Checler
F
F
Annaert
W
W
Van Broeckhoven
C
C
De Strooper
B
B
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011233:Precipitin Tests; D014161:Transduction, Genetic
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; C509282:Bace1 protein, mouse