Caspase-3 activation and inflammatory responses in rat hippocampus inoculated with a recombinant adenovirus expressing the Alzheimer amyloid precursor protein.
To elucidate the mechanism of neuronal death in Alzheimer's disease, we investigated the effects of overexpression of wild-type Alzheimer amyloid precursor protein (APP) on neuronal cells and glial cells in vivo. When an APP695-expressing adenovirus was injected into the dorsal hippocampal region, a number of neurons in remote areas were positively stained with anti-APP monoclonal antibody, and underwent severe degeneration from 3 to 7 days after viral inoculation. Most degenerating neurons were immunopositive with both APP and activated caspase-3, but some neurons that expressed activated caspase-3 were not expressing APP from 7 to 14 days after virus injection. In the neighborhood of the degenerating neurons, activated microglia/macrophages, which were identified by the phenotypic marker C3bi receptor (CD11b/c; OX-42), were observed, and some of them appeared to phagocytose the caspase-3-immunopositive degenerating neurons. In addition to microglia/macrophages, infiltrating leukocytes expressing CD45 or CD4 were also detected. These results suggest that the increased accumulation of APP induced not only caspase-3-mediated death machinery, but also inflammatory responses including microglial activation. These inflammatory responses might cause further neurodegeneration through the alternative pathway that might activate the caspase-3-mediated death machinery without APP expression.
Masumura
M
M
BF Research Institute, c/o National Cardiovascular Center, 7-1, 5-Chome, Fujishiro-dai, Suita, 565-0873, Osaka, Japan. masumura@silver.ocn.ne.jp
Hata
R
R
Nishimura
I
I
Uetsuki
T
T
Sawada
T
T
Yoshikawa
K
K
D000256:Adenoviridae / Q000235:genetics*; D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001562:Benzimidazoles; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002452:Cell Count; D004660:Encephalitis / Q000201:enzymology; D005456:Fluorescent Dyes; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D017628:Microglia / Q000276:immunology; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar
D016564:Amyloid beta-Protein Precursor; D001562:Benzimidazoles; D005456:Fluorescent Dyes; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C017807:bisbenzimide ethoxide trihydrochloride