Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo

David R. Borchelt, Gopal Thinakaran, Christopher B. Eckman, Michael K. Lee, Frances Davenport, Tamara Ratovitsky, Cristian Mihail Prada, Grace Kim, Sophia Seekins, Debra Yager, Hilda H. Slunt, Rong Wang, Mary Seeger, Allan I. Levey, Samuel E. Gandy, Neal G. Copeland, Nancy A. Jenkins, Donald L. Price, Steven G. Younkin, Sangram S. Sisodia

Research output: Contribution to journalArticle

Abstract

Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Aβ1-42(43)/Aβ1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Aβ 1-42(43)/Aβ1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Aβ peptides terminating at 42(43), species that foster Aβ deposition.

Original languageEnglish (US)
Pages (from-to)1005-1013
Number of pages9
JournalNeuron
Volume17
Issue number5
DOIs
StatePublished - Nov 1996

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., Prada, C. M., Kim, G., Seekins, S., Yager, D., Slunt, H. H., Wang, R., Seeger, M., Levey, A. I., Gandy, S. E., Copeland, N. G., Jenkins, N. A., Price, D. L., Younkin, S. G., & Sisodia, S. S. (1996). Familial Alzheimer's disease-linked presenilin I variants elevate aβ1- 42/1-40 ratio in vitro and in vivo. Neuron, 17(5), 1005-1013. https://doi.org/10.1016/S0896-6273(00)80230-5