Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: Evidence for augmentation of a 42-specific γ secretase

Joanna L. Jankowsky, Daniel J. Fadale, Jeffrey Anderson, Guilian M. Xu, Victoria Gonzales, Nancy A. Jenkins, Neal G. Copeland, Michael K. Lee, Linda H. Younkin, Steven L. Wagner, Steven G. Younkin, David R. Borchelt

Research output: Contribution to journalReview articlepeer-review

898 Scopus citations

Abstract

Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and γ-secretase to release amyloid peptides (Aβ40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Aβ40/42 is generated by γ-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in patients with early-onset familial AD (FAD), and previous studies in transgenic mice and cultured cell models demonstrated that FAD-PS1 variants shift the ratio of Aβ40 : 42 to favor Aβ42. One hypothesis to explain this outcome is that mutant PS alters the specificity of γ-secretase to favor production of Aβ42 at the expense of Aβ40. To test this hypothesis in vivo, we studied Aβ40 and 42 levels in a series of transgenic mice that co-express the Swedish mutation of APP (APPswe) with two FAD-PS1 variants that differentially accelerate amyloid pathology in the brain. We demonstrate a direct correlation between the concentration of Aβ42 and the rate of amyloid deposition. We further show that the shift in Aβ42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Aβ42, while maintaining a constant level of Aβ40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for γ-secretase, but rather that they have more complex effects on the regulation of γ-secretase and its access to substrates.

Original languageEnglish (US)
Pages (from-to)159-170
Number of pages12
JournalHuman molecular genetics
Volume13
Issue number2
DOIs
StatePublished - Jan 15 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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