SPATIAL-RESOLUTION OF THE PRIMARY BETA-AMYLOIDOGENIC PROCESS-INDUCED IN POSTISCHEMIC HIPPOCAMPUS

Proteolytic modifications of amyloid precursor protein (APP) play key roles in the development of Alzheimer's disease. However, each specifi c in vivo process has not yet been fully resolved in spatial terms bec ause the orthodox approach employing electrophoretic analysis requires homogenization of samples and thus provides limited information on th e localization of the process. To acquire such spatial information for the primary process involved in beta-amyloidogenesis, we have designe d and developed a novel antibody exclusively specific to APP fragments possessing the exact amino terminus of the major beta-amyloid (A beta ) peptide. Use of this antibody revealed that cleavage of APP at the a mino terminal position of the A beta sequence is a normal steady-state process in gerbil hippocampus. Furthermore, nonfatal transient (10 mi n) forebrain ischemia followed by reperfusion enhanced the initial bet a-amyloidogenic reaction mainly in pyramidal cells of CA1 sector and o f dentate gyrus prior to and along with delayed neuronal degeneration. The APP fragments accumulated in cell bodies and dendrites of the neu rons. These results suggest that beta-amyloidogenesis may involve a pr ocess that is also activated in postischemic brain and that ischemia-l ike conditions may contribute to pathogenic A beta accumulation.