title: Degeneration in vivo of rat hippocampal neurons by wild-type Alzheimer amyloid precursor protein overexpressed by adenovirus-mediated gene transfer.
abstract: 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 beta-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 beta/A4 protein (Abeta)-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 Abeta deposition.
authors.affiliation: Division of Regulation of Macromolecular Functions, Institute for Protein Research, Osaka University, Suita, Osaka 565, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Nishimura
authors.forename: T
authors.initials: T
authors.lastname: Uetsuki
authors.forename: S U
authors.initials: SU
authors.lastname: Dani
authors.forename: Y
authors.initials: Y
authors.lastname: Ohsawa
authors.forename: I
authors.initials: I
authors.lastname: Saito
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: Y
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: K
authors.initials: K
authors.lastname: Yoshikawa
mesh_terms: D000256:Adenoviridae; D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001710:Biotin; D053938:DNA Fragmentation; D018076:DNA, Complementary; D003856:Deoxyuracil Nucleotides; D004234:Diuretics, Osmotic / Q000494:pharmacology; D000939:Epitopes / Q000032:analysis; D005110:Extracellular Space / Q000737:chemistry; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D017628:Microglia / Q000502:physiology; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000503:physiopathology*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling; D013569:Synapses / Q000502:physiology / Q000648:ultrastructure
chemical_list: D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary; D003856:Deoxyuracil Nucleotides; D004234:Diuretics, Osmotic; D000939:Epitopes; D008353:Mannitol; D001710:Biotin