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The Journal of Neuroscience, April 1, 1998, 18(7):2387-2398

Degeneration In Vivo of Rat Hippocampal Neurons by Wild-Type Alzheimer Amyloid Precursor Protein Overexpressed by Adenovirus-Mediated Gene Transfer

Isao Nishimura¹, Taichi Uetsuki¹, Sergio U. Dani¹, Yoshiyuki Ohsawa², Izumu Saito³, Hitoshi Okamura⁴, Yasuo Uchiyama², and Kazuaki Yoshikawa¹

¹ Division of Regulation of Macromolecular Functions, Institute for Protein Research, Osaka University, Suita, Osaka 565, Japan, ² Department of Anatomy, Osaka University Medical School, Suita, Osaka 565, Japan, ³ Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108, Japan, and ⁴ Department of Anatomy and Brain Science, Kobe University School of Medicine, Chuo-ku, Kobe 650, Japan

In an attempt to elucidate the pathological implications of intracellular accumulation of the amyloid precursor protein (APP) in postmitotic neurons in vivo, we transferred APP695 cDNA into rat hippocampal neurons by using a replication-defective adenovirus vector. We first improved the efficiency of adenovirus-mediated gene transfer into neurons in vivo by using hypertonic mannitol. When a -galactosidase-expressing 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 transport of the virus. When an APP695-expressing adenovirus was injected into the same site, part of the infected neurons in the hippocampal formation underwent severe degeneration in a few days, whereas astrocytes near the injection site showed no apparent degeneration. These degenerating neurons accumulated different epitopes of APP, and /A4 protein (A)-immunoreactive materials were undetected in the extracellular space. A small number of degenerating neurons showed nuclear DNA fragmentation. Electron microscopic examinations demonstrated that degenerating neurons had shrunken perikarya along with synaptic abnormalities. Microglial cells/macrophages were often found in close proximity to degenerating neurons, and in some cases they phagocytosed these neurons. 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 deposition.

Key words: Alzheimer's disease; amyloid precursor protein; neurodegeneration; apoptosis; microglia; synapse; hippocampus; hypertonic mannitol; adenovirus vector

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1872387-12$05.00/0

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