Overexpression of a C-Terminal Portion of the β-Amyloid Precursor Protein in Mouse Brains by Transplantation of Transformed Neuronal Cells

Ken ichiro Fukuchi, Dennis D. Kunkel, Philip A Schwartzkroin, Kouzin Kamino, Charles E. Ogburn, Clement E. Furlong, George M. Martin

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The role of β-amyloid protein and its precursor protein is a central question in the pathogenesis of Alzheimer's disease. We have established several transformants from a mouse embryonic carcinoma cell line, which overproduce a C-terminal region of the β-amyloid precursor protein from the integrated DNA constructs. These stable transformants degenerated to varying extents when undergoing neural differentiation mediated by retinoic acid. To test the neurotoxicity and the amyloidogenicity of the transgene product and its proteolytic derivatives in vivo, two stable transformants were neuronally differentiated and transplanted into the hippocampal regions of syngeneic mice. Similarly, either a nontransformant or a transformant bearing a cDNA construct for yeast major apurinic endonuclease was transplanted to the contralateral regions of the same mice. Three weeks after transplantation, grafts were identified around needle tracts or in hippocampal regions. The regions where transformants overproducing the C-terminal region were grafted were highly reactive to antibodies raised against β-amyloid protein and its precursor protein, in contrast to the contralateral regions. At 2 and 5 months after neurotransplantation, remarkable distortion and shrinkage characterized the hippocampus on the sides injected with the transformants overproducing the C-terminal region. This shrinkage was associated particularly with a loss of the hippocampal granule cells. β-Amyloid protein immunoreactive granular deposits in the neuropil were also found in the same sides. Hippocampal blood vessel walls were also stained with the antibodies. These walls were surrounded by astrocytic processes, suggesting involvement of astroglial cells in vascular deposits of β-amyloid protein. The results are consistent with the hypothesis that the C-terminal region or its derivatives are neurotoxic and amyloidogenic.

Original languageEnglish (US)
Pages (from-to)253-264
Number of pages12
JournalExperimental Neurology
Volume127
Issue number2
DOIs
StatePublished - Jun 1994
Externally publishedYes

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

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