A short cytoplasmic domain of the amyloid precursor protein induces apoptosis in vitro and in vivo.
The amyloid precursor protein presents several cleavage sites leading to the release of its entire C-terminal domain into the cytoplasm. During apoptosis, this C-terminal domain can be cleaved at amino acid 664 by caspases 3, 6, and 8 and can thus generate two peptides N- and C-terminal to amino acid 664 (C31). Recently, it was shown that the C31 induces apoptosis after transfection into N2A and 293 T cell lines. We have analyzed here, by internalization into neurons, the physiological consequences of the entire C-terminal domain (APP-Cter) and of its membrane proximal sequence corresponding to the N-terminal peptide unmasked after caspase cleavage. We find that whereas micromolar concentrations of APP-Cter are harmless, the peptide extending from the membrane (amino acid 649) to the caspase cleavage site (amino acid 664) in the same range of concentrations induces DNA fragmentation, cleavage of actin at a caspase-sensitive site, and activates caspase 3. A mutated version of this sequence (tyrosine 653 replaced by an aspartate) abolishes the effect in vitro and in vivo. Taken together, this report suggests the existence of a new mechanism contributing to Alzheimer's Disease-associated cell death.
Bertrand
E
E
Centre National de la Recherche de Scientifique UMR 8542, Ecole normale supérieure, Paris, France.
Brouillet
E
E
Caillé
I
I
Bouillot
C
C
Cole
G M
GM
Prochiantz
A
A
Allinquant
B
B
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000502:physiology; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D010455:Peptides; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse