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The Journal of Neuroscience, August 15, 1999, 19(16):6955-6964
Activation of Neuronal Caspase-3 by Intracellular Accumulation of
Wild-Type Alzheimer Amyloid Precursor Protein
Taichi
Uetsuki1,
Kiwamu
Takemoto1,
Isao
Nishimura1,
Mariko
Okamoto1,
Michio
Niinobe1,
Takashi
Momoi2,
Masayuki
Miura3, and
Kazuaki
Yoshikawa1
1 Division of Regulation of Macromolecular Functions,
Institute for Protein Research, Osaka University, Yamadaoka 3-2,
Suita, Osaka 565-0871, Japan, 2 Division of Development
and Differentiation, National Institute of Neuroscience, National
Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan,
and 3 Department of Neuroanatomy, Biomedical Research
Center, Osaka University Medical School, Yamadaoka 2-2, Suita, Osaka
565-0871, Japan
Forced overexpression of wild-type Alzheimer amyloid precursor
protein (APP) causes postmitotic neurons to degenerate. Caspase-3 (CPP32) is a principal cell death protease involved in neuronal apoptosis during physiological development and under pathological conditions. Here, we investigated whether APP overexpression activates caspase-3 in human postmitotic neurons using adenovirus-mediated gene
transfer. When a recombinant adenovirus vector expressing human
wild-type APP695 was infected in vitro into neurally
differentiated embryonal carcinoma NT2 cells, only postmitotic neurons
underwent severe degeneration. Before neurodegeneration, full-length
APP- and A -immunoreactive peptides were accumulated in infected
neurons, and caspase-3-like protease activity was markedly elevated.
Western blot analysis revealed that activated caspase-3 subunits
were generated in APP-accumulating neurons. Such neuronal caspase-3 activation was undetectable in NT2 neurons infected with
-galactosidase-expressing adenovirus. Addition of the caspase-3
inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde to the culture medium
significantly reduced the severity of degeneration exhibited by
APP-overexpressing neurons. Immunocytochemical analyses revealed that
some APP-accumulating neurons contained activated caspase-3 subunits
and exhibited the characteristics of apoptosis, such as chromatin
condensation and DNA fragmentation. Activation of caspase-3 was also
observed in vivo in rat hippocampal neurons infected
with the APP-expressing adenovirus. These results suggest that
wild-type APP is an intrinsic activator of caspase-3-mediated death
machinery in postmitotic neurons.
Key words:
amyloid precursor protein; caspase-3; apoptosis; adenovirus vector; postmitotic neurons; Alzheimer's disease
Copyright © 1999 Society for Neuroscience 0270-6474/99/19166955-10$05.00/0
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