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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. and Fadale, Daniel J. and Anderson, Jeffrey and Xu, Guilian M. and Gonzales, Victoria and Jenkins, Nancy A. and Copeland, Neal G. and Lee, Michael K. and Younkin, Linda H. and Wagner, Steven L. and Younkin, Steven G. and Borchelt, David R. (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, 13 (2). pp. 159-170. ISSN 0964-6906. doi:10.1093/hmg/ddh019.

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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.

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Additional Information:© 2004 Oxford University Press. Received August 15, 2003; Revised and Accepted November 11, 2003. First published online: November 25, 2003. We thank Debbie Swing for assistance with the production of transgenic mice, and David Fromholt and Alvin George for help with mouse genotyping. Data on crosses of Mo/Hu APPswe line C3-3 to PS1-dE9 line O-7 were kindly provided by Drs. Shadid Zaman, Flavio Kamenetz, and Roberto Malinow (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA). We are grateful to Drs Konrad Beyreuther and Andreas Weidemann for sharing the 22C11 antibody, and to Dr Robert Siman (University of Pennsylvania Medical School) for sharing the anti-SEVNL antibody. This work was funded by grants from the National Institute of Aging (D.R.B.; NIA 1 P50 AG 14248 and NIA 1 P01 AG-98-003), the National Cancer Institute (N.A.J. and N.G.C.), and the Alzheimer’s Association (D.R.B.). J.L.J. was supported by a training grant (NIH 1 T32 NS 07435), and by funding from the John Douglas French Alzheimer’s Foundation and the American Health Assistance Foundation.
Funding AgencyGrant Number
NIH1 P50 AG 14248
NIH1 P01 AG-98-003
National Cancer InstituteUNSPECIFIED
Alzheimer's AssociationUNSPECIFIED
NIH Predoctoral Fellowship1 T32 NS 07435
John Douglas French Alzheimer’s FoundationUNSPECIFIED
American Health Assistance FoundationUNSPECIFIED
Issue or Number:2
Record Number:CaltechAUTHORS:20111014-072743710
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Official Citation: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, and David R. Borchelt Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase Hum. Mol. Genet. (2004) 13(2): 159-170 first published online November 25, 2003 doi:10.1093/hmg/ddh019
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27220
Deposited By: Ruth Sustaita
Deposited On:14 Oct 2011 15:01
Last Modified:09 Nov 2021 16:46

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