Cell death induced by a caspase-cleaved transmembrane fragment of the Alzheimer amyloid precursor protein.
The Alzheimer amyloid precursor protein (APP) is a transmembrane protein whose abnormal processing is associated with the pathogenesis of Alzheimer's disease. Activated caspases cleave APP and generate its carboxyl-terminally truncated fragment (APPdeltaC31). We have previously reported that overexpression of wild-type APP induces caspase-3 activation and apoptosis in postmitotic neurons. We now report that APPdeltaC31 potentially plays pathophysiological roles in neuronal death. Adenovirus-mediated overexpression of wild-type APP695 induced activation of caspase-3 and accumulation of APPdeltaC31 in postmitotic neurons derived from human NT2 embryonal carcinoma cells, whereas an APP mutant lacking the Abeta(1-20) region induced neither caspase-3 activation nor APPdeltaC31 generation. Inhibition of caspase-3 suppressed the generation of APPdeltaC31 in APP-overexpressing neurons. Forced expression of APPdeltaC31 induced apoptotic changes of neurons and non-neuronal cells, but failed to activate caspase-3. The cytotoxicity of APPdeltaC31 was also dependent on the Abeta(1-20) region. These results suggest that accumulation of wild-type APP activates neuronal caspase-3 to generate APPdeltaC31 that mediates caspase-3-independent cell death.
Nishimura
I
I
Division of Regulation of Macromolecular Functions, Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan.
Uetsuki
T
T
Kuwako
K
K
Hara
T
T
Kawakami
T
T
Aimoto
S
S
Yoshikawa
K
K
D000256:Adenoviridae / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism* / Q000502:physiology; D016895:Culture Media, Serum-Free; D006801:Humans; D007150:Immunohistochemistry; D008938:Mitosis; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D010446:Peptide Fragments / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D016895:Culture Media, Serum-Free; D010446:Peptide Fragments; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases