In order to study the properties of β-amyloid in vivo, we generated a total of 28 transgenic founder mice that harbored the gene for the 17-amino acid signal sequence and the 99-amino acid carboxy-terminal fragment (CTF) of the human amyloid-β protein precursor (βAPP) linked to the cytomegalovirus enhancer and chicken β-actin promoter. Two of these founders, termed 0304 and 0809, exhibited decreased behavioral activity with gliosis and neurodegeneration in the hippocampus at 2.5 and 9 months of age. Both mice had also decreased levels of synaptophysin, a presynaptic marker, but no evidence for β-amyloid deposition in their brains. Neurodegeneration in the hippocampus was transmitted to the offspring of mouse 0304, although the frequency was low (5 of 44 mice examined) and the time of onset of the disorder was rather later than that in the founder mouse. This is probably due to reduced levels of the transgene-derived products in the offspring of mouse 0304. The 0809 line failed to produce its offspring. The other remaining transgenic founders appeared normal and had lesser amounts of the CTF mRNA and protein in their brains than did 0304 and 0809 founders, though some mice died in earlier stages or exhibited hydrocephalus. These findings suggest that overexpression of the CTF of human βAPP has the potential to elicit neurodegeneration in vivo without appreciable production of β-amyloid fibrils.

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