DISCOVERY OF A BRAIN PROMOTER FROM THE HUMAN TRANSFERRIN GENE AND ITSUTILIZATION FOR DEVELOPMENT OF TRANSGENIC MICE THAT EXPRESS HUMAN APOLIPOPROTEIN-E ALLELES

Transgenic mice carrying heterologous genes directed by a 670-bp segme nt of the regulatory sequence from the human transferrin (TF) gene dem onstrated high expression in brain, Mice carrying the chimeric 0.67kbT F-CAT gene expressed TF-CAT in neurons and glial cells of the nucleus basalis, the cerebrum, corpus callosum, cerebellum, and hippocampus. I n brains from two independent TF-CAT transgenic founder lines, copy nu mber of TF-CAT mRNA exceeded the number of mRNA transcripts encoding e ither mouse endogenous transferrin or mouse endogenous amyloid precurs or protein, In two transgenic founder lines, the chloramphenicol acety ltransferase (CAT) protein synthesized from the TF-CAT mRNA was estima ted to be 0.10-0.15% of the total soluble proteins of the brain, High expression observed in brain indicates that the 0.67kbTF promoter is a promising director of brain expression of heterologous genes, Therefo re, the promoter has been used to express the three common human apoli poprotein E (apoE) alleles in transgenic mouse brains, The apoE allele s have been implicated in the expression of Alzheimer disease, and the human apoE isoforms are reported to interact with different affinitie s to the brain beta-amyloid and tau protein in vitro. Results of this study demonstrate high expression and production of human apoE protein s in transgenic mouse brains, The model may be used to characterize th e interaction of human apoE isoforms with other brain proteins and pro vide information helpful in designing therapeutic strategies for Alzhe imer disease.