OVEREXPRESSION OF A C-TERMINAL PORTION OF THE BETA-AMYLOID PRECURSOR PROTEIN IN MOUSE BRAINS BY TRANSPLANTATION OF TRANSFORMED NEURONAL CELLS

The role of beta-amyloid protein and its precursor protein is a centra l question in the pathogenesis of Alzheimer's disease. We have establi shed several transformants from a mouse embryonic carcinoma cell line, which overproduce a C-terminal region of the beta-amyloid precursor p rotein 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 amyloidog enicity of the transgene product and its proteolytic derivatives in vi vo, two stable transformants were neuronally differentiated and transp lanted into the hippocampal regions of syngeneic mice. Similarly, eith er a nontransformant or a transformant bearing a cDNA construct for ye ast major apurinic endonuclease was transplanted to the contralateral regions of the same mice. Three weeks after transplantation, grafts we re identified around needle tracts or in hippocampal regions. The regi ons where transformants overproducing the C-terminal region were graft ed were highly reactive to antibodies raised against beta-amyloid prot ein and its precursor protein, in contrast to the contralateral region s. At 2 and 5 months after neurotransplantation, remarkable distortion and shrinkage characterized the hippocampus on the sides injected wit h the transformants overproducing the C-terminal region. This shrinkag e was associated particularly with a loss of the hippocampal granule c ells. beta-Amyloid protein immunoreactive granular deposits in the neu ropil were also found in the same sides. Hippocampal blood vessel wall s were also stained with the antibodies. These walls were surrounded b y astrocytic processes, suggesting involvement of astroglial cells in vascular deposits of beta-amyloid protein. The results are consistent with the hypothesis that the C-terminal region or its derivatives are neurotoxic and amyloidogenic. (C) 1994 Academic Press, Inc.