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 th e release of its entire C-terminal domain into the cytoplasm. During apopto sis, 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 aci d 664 (C31). Recently, it was shown that the C31 induces apoptosis after tr ansfection into N2A and 293 T cell lines. We have analyzed here, by interna lization into neurons, the physiological consequences of the entire C-termi nal domain (APP-Cter) and of its membrane proximal sequence corresponding t o the N-terminal peptide unmasked after caspase cleavage. We find that wher eas micromolar concentrations of APP-Cter are harmless, the peptide extendi ng from the membrane (amino acid 649) to the caspase cleavage site (amino a cid 664) in the same range of concentrations induces DNA fragmentation, cle avage of actin at a caspase-sensitive site, and activates caspase 3. A muta ted version of this sequence (tyrosine 653 replaced by an aspartate) abolis hes the effect in vitro and in vivo. Taken together, this report suggests t he existence of a new mechanism contributing to Alzheimer's Disease-associa ted cell death.