ABSTRACT
Alzheimer's disease is characterized by widespread deposition of amyloid in the central nervous system. The 4-kilodalton amyloid beta protein is derived from a larger amyloid precursor protein and forms amyloid deposits in the brain by an unknown pathological mechanism. Except for aged nonhuman primates, there is no animal model for Alzheimer's disease. Transgenic mice expressing amyloid beta protein in the brain could provide such a model. To investigate this possibility, the 4-kilodalton human amyloid beta protein was expressed under the control of the promoter of the human amyloid precursor protein in two lines of transgenic mice. Amyloid beta protein accumulated in the dendrites of some but not all hippocampal neurons in 1-year-old transgenic mice. Aggregates of the amyloid beta protein formed amyloid-like fibrils that are similar in appearance to those in the brains of patients with Alzheimer's disease.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Peptides/genetics , Brain/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/analysis , Animals , Base Sequence , Brain/pathology , DNA/genetics , Hippocampus/ultrastructure , Humans , Mice , Mice, Transgenic , Microscopy, Electron , Molecular Sequence Data , Neurofibrils/ultrastructure , Oligonucleotide Probes , Restriction MappingABSTRACT
During myogenesis, induction of muscle-specific genes is subject to negative control by polypeptide mitogens and type-beta transforming growth factor. Since transduction of growth factor signals may require proteins encoded by cellular ras oncogenes, we have tested whether a mutationally altered Harvey ras expression vector, by itself, can prevent establishment of a differentiated phenotype in BC3H1 mouse myoblasts. Transfection with the valine-12 allele of the human Harvey ras gene, under the control of its own promoter, was sufficient to prevent the induction of both muscle creatine kinase activity and the nicotinic acetylcholine receptor following mitogen withdrawal but did not inhibit withdrawal from the cell cycle. The loss of creatine kinase activity resulted from a corresponding block to induction of muscle creatine kinase mRNA. Similarly, mitogen withdrawal elicited little or no alpha-actin mRNA in ras-transfected cells. These results suggest that an activated ras allele can inhibit myogenesis through a mechanism independent of cell proliferation and can preclude activation of genes whose up-regulation normally accompanies mitogen withdrawal.
