Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice

George A. Carlson, David R. Borchelt, Angela Dake, Sherry Turner, Valerie Danielson, J. Douglas Coffin, Chris Eckman, James Meiners, Steven P. Nilsen, Steven G. Younkin, Karen K. Hsiao

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148 Scopus citations

Abstract

Overexpression of Alzheimer amyloid precursor protein (APP) produces dramatically different phenotypes in transgenic mice depending on the genetic background. For example, concentrations of APP that produce amyloid plaques in outbred transgenic lines are lethal for inbred FVB/N or C57BL/6J mice. Expression of SOD1 transgenes is protective, suggesting involvement of oxidative damage in premature death, but ablation of Apoe had no significant effect. In contrast, FGF2 transgene overexpression enhances the lethal effects of APP. Differential survival does not appear to reflect genetic differences in APP processing, but rather host responses to APP or its derivatives.

Original languageEnglish (US)
Pages (from-to)1951-1959
Number of pages9
JournalHuman molecular genetics
Volume6
Issue number11
DOIs
StatePublished - Oct 1997

Bibliographical note

Funding Information:
We thank Stanley B. Prusiner and Michael Scott for the cosTet transgene expression vector and for their advice. We are very grateful to Philip Wong for providing the human SOD1 transgenic animals, and to Debbie Swing, Nancy Jenkins and Neal Copeland for their assistance in generating these mice. Gratitude is also due to Donald Price and Judy Van Lare for their assistance in neuropathology, and to William R. Crain and John Mercer for helpful discussions. This work was supported by grants AG10681 (G.A.C.), AG07914 (D.R.B.), AG12685 (S.Y.) and NS33249 (K.H.) from the National Institutes of Health, from the Alzheimer’s Association (D.R.B. and S.Y.), from the Fraternal Order of Eagles (G.A.C.) and from the American Health Assistance Foundation (S.Y.). V.D. was awarded a summer research fellowship from the Dennis and Phyllis Washington Foundation.

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