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 journalArticle

780 Citations (Scopus)

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

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Presenilins
Amyloid Precursor Protein Secretases
Amyloid
Peptides
Alzheimer Disease
Amyloid beta-Protein Precursor
Transgenic Mice
Presenilin-2
Presenilin-1
Amyloid Plaques
Brain
Missense Mutation
Cultured Cells
Pathology
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo : Evidence for augmentation of a 42-specific γ secretase. / Jankowsky, Joanna L.; Fadale, Daniel J.; Anderson, Jeffrey; Xu, Guilian M.; Gonzales, Victoria; Jenkins, Nancy A.; Copeland, Neal G.; Lee, Michael K.; Younkin, Linda H.; Wagner, Steven L.; Younkin, Steven G; Borchelt, David R.

In: Human Molecular Genetics, Vol. 13, No. 2, 15.01.2004, p. 159-170.

Research output: Contribution to journalArticle

Jankowsky, JL, Fadale, DJ, Anderson, J, Xu, GM, Gonzales, V, Jenkins, NA, Copeland, NG, Lee, MK, Younkin, LH, Wagner, SL, Younkin, SG & Borchelt, DR 2004, 'Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: Evidence for augmentation of a 42-specific γ secretase', Human Molecular Genetics, vol. 13, no. 2, pp. 159-170. https://doi.org/10.1093/hmg/ddh019
Jankowsky, Joanna L. ; Fadale, Daniel J. ; Anderson, Jeffrey ; Xu, Guilian M. ; Gonzales, Victoria ; Jenkins, Nancy A. ; Copeland, Neal G. ; Lee, Michael K. ; Younkin, Linda H. ; Wagner, Steven L. ; Younkin, Steven G ; Borchelt, David R. / Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo : Evidence for augmentation of a 42-specific γ secretase. In: Human Molecular Genetics. 2004 ; Vol. 13, No. 2. pp. 159-170.
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AU - Gonzales, Victoria

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AU - Copeland, Neal G.

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