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 specific in vivo process has not yet been fully resolved in spatial terms because the orthodox approach employing electrophoretic analysis requires homogenization of samples and thus provides limited information on the localization of the process. To acquire such spatial information for the primary process involved in beta-amyloidogenesis, we have designed 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 amino terminal position of the A beta sequence is a normal steady-state process in gerbil hippocampus. Furthermore, nonfatal transient (10 min) forebrain ischemia followed by reperfusion enhanced the initial beta-amyloidogenic reaction mainly in pyramidal cells of CA1 sector and of dentate gyrus prior to and along with delayed neuronal degeneration. The APP fragments accumulated in cell bodies and dendrites of the neurons. These results suggest that beta-amyloidogenesis may involve a process that is also activated in postischemic brain and that ischemia-like conditions may contribute to pathogenic A beta accumulation.