Rodent Aβ modulates the solubility and distribution of amyloid deposits in transgenic mice

Joanna L. Jankowsky, Linda H. Younkin, Victoria Gonzales, Daniel J. Fadale, Hilda H. Slunt, Henry A. Lester, Steven G. Younkin, David R. Borchelt

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

The amino acid sequence of amyloid precursor protein (APP) is highly conserved, and age-related Aβ aggregates have been described in a variety of vertebrate animals, with the notable exception of mice and rats. Three amino acid substitutions distinguish mouse and human Aβ that might contribute to their differing properties in vivo. To examine the amyloidogenic potential of mouse Aβ, we studied several lines of transgenic mice overexpressing wild-type mouse amyloid precursor protein (moAPP) either alone or in conjunction with mutant PS1 (PS1dE9). Neither overexpression of moAPP alone nor co-expression with PS1dE9 caused mice to develop Alzheimer-type amyloid pathology by 24 months of age. We further tested whether mouse Aβ could accelerate the deposition of human Aβ by crossing the moAPP transgenic mice to a bigenic line expressing human APPswe with PS1dE9. The triple transgenic animals (moAPP x APPswe/PS1dE9) produced 20% more Aβ but formed amyloid deposits no faster and to no greater extent than APPswe/PS1dE9 siblings. Instead, the additional mouse Aβ increased the detergent solubility of accumulated amyloid and exacerbated amyloid deposition in the vasculature. These findings suggest that, although mouse Aβ does not influence the rate of amyloid formation, the incorporation of Aβ peptides with differing sequences alters the solubility and localization of the resulting aggregates.

Original languageEnglish (US)
Pages (from-to)22707-22720
Number of pages14
JournalJournal of Biological Chemistry
Volume282
Issue number31
DOIs
StatePublished - Aug 3 2007

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Jankowsky, J. L., Younkin, L. H., Gonzales, V., Fadale, D. J., Slunt, H. H., Lester, H. A., Younkin, S. G., & Borchelt, D. R. (2007). Rodent Aβ modulates the solubility and distribution of amyloid deposits in transgenic mice. Journal of Biological Chemistry, 282(31), 22707-22720. https://doi.org/10.1074/jbc.M611050200