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 inv estigated the effects of overexpression of wild-type Alzheimer amyloid prec ursor protein (APP) on neuronal cells and glial cells in vivo. When an APP6 95-expressing adenovirus was injected into the dorsal hippocampal region, a number of neurons in remote areas were positively stained with anti-APP mo noclonal 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 cas pase-3 were not expressing APP from 7 to 14 days after virus injection. In the neighborhood of the degenerating neurons, activated microglia/macrophag es, 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/macrophage s, infiltrating leukocytes expressing CD45 or CD-C were also detected. Thes e results suggest that time increased accumulation of APP induced not only caspase-3-mediated death machinery, but also inflammatory responses includi ng microglial activation. These inflammatory responses might cause further neurodegeneration through the alternative pathway that might activate the c aspase-3-mediated death machinery without APP expression (C) 2000 Elsevier Science B.V. All rights reserved.