George Scangos

Regulatory region of human amyloid precursor protein (APP) gene promotes neuron-specific gene expression in the CNS of transgenic mice

The accumulation of beta‐amyloid protein in specific brain regions is a central pathological feature of Alzheimers disease (AD). The 4 kd beta‐amyloid protein derives from a larger amyloid precursor protein (APP) by as yet unknown mechanisms. In the absence of a laboratory animal model of AD, transgenic mice expressing various APP gene products may provide new insights into the relationship between APP and beta‐amyloid formation and the pathogenesis of AD. beta‐amyloid accumulation in AD brain may result from interactions between APP and other molecules. Such interactions are likely to be developmentally regulated and tissue‐specific. A transgenic mouse model of AD, therefore, would aim for APP transgene expression that mimics the endogenous APP gene. As an initial step in developing an animal model, we have identified a 4.5 kb DNA fragment from the 5′ end of the human APP gene, which mediates neuron‐specific gene expression in the CNS of transgenic mice, using E. coli lacZ as a reporter gene. Detectable levels of transgene expression are found in most neurons but not in glial and vascular endothelial cells. The expression pattern of this reporter gene closely resembles the distribution of endogenous APP mRNA in both the human and mouse CNS.

Regulation and genetic control of brain amyloid

D. Carleton Gajdusek, Konrad Beyreuther, Paul Brown, Linda C. Cork, Dennis D. Cunningham, Bias Frangione, C.J. Gibbs Jr., Lev G. Goldfarb, D. Goldgaber, Karen K. Hsiao, Edward H. Koo, Lee J. Martin, Colin L. Masters, W.F. Odenwald, Donald L. Price, S.B. Prusiner, Frank H. Ruddle, Jiri Safar, George Scangos, D.E. Schmechel, Cooduvalli S. Shashikant, Paul J. Shlichta, Sangram S. Sisodia, Bruce D. Trapp, Axe1 Unterbeck, William E. Van Nostrand, Shelia M. Violette, Lary C. Walker and Dana Wirak

Differential effects on T cell and NK cell development by tissue-specific expression of H-2D(d) transgene

The effect of tissue‐specific expression of the MHC class I molecule H‐2Dd on T cell and NK cell specificity was studied in transgenic mice expressing the H‐2Dd gene under the control of the mouse metallothionein‐I promoter. MTD mice expressed high amounts of H‐2Dd in the liver, intestine and testis, but only minute amounts in the thymus, spleen and kidney. Zinc administration resulted in a 1.5‐ and 8.5‐fold increase in H‐2Dd expression in the liver and the intestine, respectively, but did not affect expression in the other organs tested. T cell tolerance developed towards H‐2Dd in MTD mice, even in the absence of zinc. In contrast, NK cell‐mediated natural resistance against lymphoma grafts was not seen in MTD mice, despite zinc administration. NK cells in MTD mice also failed to develop self tolerance to H‐2Dd. The lack of functional effects did not result from inability of NK cells in MTD mice to interact with H‐2Dd, as down‐regulation of Ly49A receptor expression was observed on liver NK cells in MTD mice. Our data reveal a difference between T cells and NK cells in their requirements for MHC class I molecules in specificity development.