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Suppression of the caspase cleavage of β‐amyloid precursor protein by its cytoplasmic phosphorylation
Author(s) -
Taru Hidenori,
Yoshikawa Kazuaki,
Suzuki Toshiharu
Publication year - 2004
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.04.077
Subject(s) - phosphorylation , amyloid precursor protein , amyloid precursor protein secretase , caspase , senile plaques , microbiology and biotechnology , chemistry , cleavage (geology) , biochemistry of alzheimer's disease , caspase 3 , transmembrane protein , p3 peptide , neurotoxicity , alpha secretase , apoptosis , biochemistry , biology , alzheimer's disease , programmed cell death , medicine , toxicity , paleontology , receptor , disease , organic chemistry , fracture (geology)
β‐Amyloid precursor protein (APP) is a type I transmembrane protein. Its cleavages by β‐ and γ‐secretases yield β‐amyloid, which is the main constituent of senile plaques in Alzheimer's disease (AD). In apoptotic cells and AD brains, APP is alternatively cleaved by caspases in the cytoplasmic region after the Asp664 residue (with respect to the numbering conversion for the APP695 isoform). Caspase‐cleaved fragments of APP are cytotoxic and have been implicated in AD pathogenesis; however, the mechanisms regulating the cleavage have not been studied. APP is constitutively phosphorylated at Thr668 in brain. In the present study, we demonstrate that APP phosphorylated at Thr668 is less vulnerable to cytoplasmic cleavage by caspase‐3 and caspase‐8. This suggests that APP phosphorylation suppresses the generation of caspase‐cleaved fragments of APP in the brain and that perturbation of this phosphorylation may be involved in APP‐mediated neurotoxicity.