Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression

Joseph Krezowski, Danielle Knudson, Christine Ebeling, Rose Pitstick, Ranjit K. Giri, Dale Schenk, David Westaway, Linda Younkin, Stven G. Younkin, Karen H Ashe, George A. Carlson

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Phenotypes produced by expression of human amyloid precursor protein (APP) transgenes vary depending on the genetic background of the mouse. FVB/N mice overexpressing human APP695 develop a central nervous system disorder and die prematurely, precluding development of Aβ peptide amyloid plaques. 129S6 mice are resistant to the lethal effects of APP overexpression, allowing sufficient levels of Aβ expression for the development of amyloid plaques and age-dependent memory deficits. To identify the genes that determine susceptibility or resistance to APP we analyzed crosses involving FVB /NCr and 129S6.Tg2576 mice that overexpress 'Swedish' mutant (K670N, M671L) APP695. APP transgene-positive FVB129S6F1 (F1) mice are resistant to the lethal effects of APP overexpression, so FVB X F1 backcross and F2 intercross offspring were produced. Analysis of age of death as a quantitative trait revealed significant linkage to loci on proximal chromosome 14 and on chromosome 9; 129S6 alleles protect against the lethal effects of APP. Within the chromosome 14 interval are segments homologous to regions on human chromosome 10 that have been linked to late onset Alzheimer's disease or to levels of Aβ peptide in plasma. However, analysis of plasma Aβ peptide concentrations at 6 weeks in backcross offspring produced no significant linkage. Similarly, elevation of human Aβ peptide concentrations by expression of mutant presenilin transgenes did not increase the proportion of mice dying prematurely, suggesting that early death reflects effects of APP or fragments other than Aβ.

Original languageEnglish (US)
Pages (from-to)1989-1997
Number of pages9
JournalHuman molecular genetics
Volume13
Issue number18
DOIs
StatePublished - Sep 15 2004

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Amyloid beta-Protein Precursor
Transgenes
Chromosomes, Human, Pair 14
Peptides
Amyloid Plaques
Presenilins
Chromosomes, Human, Pair 10
Chromosomes, Human, Pair 9
Central Nervous System Diseases
Memory Disorders
Human Chromosomes
Alzheimer Disease
Alleles
Phenotype
Genes

Cite this

Krezowski, J., Knudson, D., Ebeling, C., Pitstick, R., Giri, R. K., Schenk, D., ... Carlson, G. A. (2004). Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. Human molecular genetics, 13(18), 1989-1997. https://doi.org/10.1093/hmg/ddh210

Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. / Krezowski, Joseph; Knudson, Danielle; Ebeling, Christine; Pitstick, Rose; Giri, Ranjit K.; Schenk, Dale; Westaway, David; Younkin, Linda; Younkin, Stven G.; Ashe, Karen H; Carlson, George A.

In: Human molecular genetics, Vol. 13, No. 18, 15.09.2004, p. 1989-1997.

Research output: Contribution to journalArticle

Krezowski, J, Knudson, D, Ebeling, C, Pitstick, R, Giri, RK, Schenk, D, Westaway, D, Younkin, L, Younkin, SG, Ashe, KH & Carlson, GA 2004, 'Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression', Human molecular genetics, vol. 13, no. 18, pp. 1989-1997. https://doi.org/10.1093/hmg/ddh210
Krezowski, Joseph ; Knudson, Danielle ; Ebeling, Christine ; Pitstick, Rose ; Giri, Ranjit K. ; Schenk, Dale ; Westaway, David ; Younkin, Linda ; Younkin, Stven G. ; Ashe, Karen H ; Carlson, George A. / Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. In: Human molecular genetics. 2004 ; Vol. 13, No. 18. pp. 1989-1997.
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