DEGENERATION IN-VIVO OF RAT HIPPOCAMPAL-NEURONS BY WILD-TYPE ALZHEIMER AMYLOID PRECURSOR PROTEIN OVEREXPRESSED BY ADENOVIRUS-MEDIATED GENE-TRANSFER

In an attempt to elucidate the pathological implications of intracellu lar accumulation of the amyloid precursor protein (APP) in postmitotic neurons in vivo, we transferred APP695 cDNA into rat hippocampal neur ons by using a replication-defective adenovirus vector. We first impro ved the efficiency of adenovirus-mediated gene transfer into neurons i n vivo by using hypertonic mannitol. When a beta-galactosidase-express ing recombinant adenovirus suspended in 1 M mannitol was injected into a dorsal hippocampal region, a number of neurons in remote areas were positively stained, presumably owing to increased retrograde transpor t of the virus. When an APP695-expressing adenovirus was injected into the same site, part of the infected neurons in the hippocampal format ion underwent severe degeneration in a few days, whereas astrocytes ne ar the injection site showed no apparent degeneration. These degenerat ing neurons accumulated different epitopes of APP, and beta/A4 protein (A beta)-immunoreactive materials were undetected in the extracellula r space. A small number of degenerating neurons showed nuclear DNA fra gmentation. Electron microscopic examinations demonstrated that degene rating neurons had shrunken perikarya along with synaptic abnormalitie s. Microglial cells/macrophages were often found in close proximity to degenerating neurons, and in some cases they phagocytosed these neuro ns. These results suggest that intracellular accumulation of wild-type APP695 causes a specific type of neuronal degeneration in vivo in the absence of extracellular A beta deposition.