Skip Navigation


Human Molecular Genetics Advance Access originally published online on November 25, 2003
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Material
Right arrow All Versions of this Article:
13/2/159    most recent
ddh019v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (70)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Jankowsky, J. L.
Right arrow Articles by Borchelt, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jankowsky, J. L.
Right arrow Articles by Borchelt, D. R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2004, Vol. 13, No. 2 159-170
DOI: 10.1093/hmg/ddh019

Mutant presenilins specifically elevate the levels of the 42 residue ß-amyloid peptide in vivo: evidence for augmentation of a 42-specific {gamma} secretase

Joanna L. Jankowsky1,{dagger}, Daniel J. Fadale3, Jeffrey Anderson4, Guilian M. Xu1, Victoria Gonzales1, Nancy A. Jenkins5, Neal G. Copeland5, Michael K. Lee1, Linda H. Younkin3, Steven L. Wagner4,6, Steven G. Younkin3 and David R. Borchelt1,2,*

1Department of Pathology and 2Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, 3Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA, 4Merck Research Labs, San Diego, 505 Coast Boulevard South, La Jolla, CA 92037, USA, 5Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA and 6Neurogenetics Inc., 11085 North Torrey Pines Road, Suite 300, La Jolla, CA 92037, USA

Received August 15, 2003; Accepted November 11, 2003

Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and {gamma}-secretase to release amyloid peptides (Aß40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Aß40/42 is generated by {gamma}-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 Aß40 : 42 to favor Aß42. One hypothesis to explain this outcome is that mutant PS alters the specificity of {gamma}-secretase to favor production of Aß42 at the expense of Aß40. To test this hypothesis in vivo, we studied Aß40 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 Aß42 and the rate of amyloid deposition. We further show that the shift in Aß42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Aß42, while maintaining a constant level of Aß40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for {gamma}-secretase, but rather that they have more complex effects on the regulation of {gamma}-secretase and its access to substrates.

* To whom correspondence should be addressed at: Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Ave, Baltimore, MD 21205, USA. Tel: +1 4105025174; Fax: +1 4109559777; Email: drbor{at}jhmi.edu


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Neurosci.Home page
S. E. Hickman, E. K. Allison, and J. El Khoury
Microglial Dysfunction and Defective {beta}-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice
J. Neurosci., August 13, 2008; 28(33): 8354 - 8360.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
S. S. El-Amouri, H. Zhu, J. Yu, R. Marr, I. M. Verma, and M. S. Kindy
Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease
Am. J. Pathol., May 1, 2008; 172(5): 1342 - 1354.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Cao, H. Lu, T. L. Lewis, and L. Li
Intake of Sucrose-sweetened Water Induces Insulin Resistance and Exacerbates Memory Deficits and Amyloidosis in a Transgenic Mouse Model of Alzheimer Disease
J. Biol. Chem., December 14, 2007; 282(50): 36275 - 36282.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Hoshino, T. Nakaya, T. Homan, K.-i. Tanaka, Y. Sugimoto, W. Araki, M. Narita, S. Narumiya, T. Suzuki, and T. Mizushima
Involvement of Prostaglandin E2 in Production of Amyloid-beta Peptides Both in Vitro and in Vivo
J. Biol. Chem., November 9, 2007; 282(45): 32676 - 32688.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Czirr, S. Leuchtenberger, C. Dorner-Ciossek, A. Schneider, M. Jucker, E. H. Koo, C. U. Pietrzik, K. Baumann, and S. Weggen
Insensitivity to Abeta42-lowering Nonsteroidal Anti-inflammatory Drugs and {gamma}-Secretase Inhibitors Is Common among Aggressive Presenilin-1 Mutations
J. Biol. Chem., August 24, 2007; 282(34): 24504 - 24513.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. L. Jankowsky, L. H. Younkin, V. Gonzales, D. J. Fadale, H. H. Slunt, H. A. Lester, S. G. Younkin, and D. R. Borchelt
Rodent Abeta Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice
J. Biol. Chem., August 3, 2007; 282(31): 22707 - 22720.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
L. Verret, J. L. Jankowsky, G. M. Xu, D. R. Borchelt, and C. Rampon
Alzheimer's-Type Amyloidosis in Transgenic Mice Impairs Survival of Newborn Neurons Derived from Adult Hippocampal Neurogenesis
J. Neurosci., June 20, 2007; 27(25): 6771 - 6780.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
T. M. Malm, H. Iivonen, G. Goldsteins, V. Keksa-Goldsteine, T. Ahtoniemi, K. Kanninen, A. Salminen, S. Auriola, T. Van Groen, H. Tanila, et al.
Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting {beta}-Amyloid Burden
J. Neurosci., April 4, 2007; 27(14): 3712 - 3721.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
J. Bao, C. Cao, X. Zhang, F. Jiang, S. V. Nicosia, and W. Bai
Suppression of {beta}-Amyloid Precursor Protein Signaling into the Nucleus by Estrogens Mediated through Complex Formation between the Estrogen Receptor and Fe65
Mol. Cell. Biol., February 15, 2007; 27(4): 1321 - 1333.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
K. Tahara, H.-D. Kim, J.-J. Jin, J. A. Maxwell, L. Li, and K.-i. Fukuchi
Role of toll-like receptor signalling in A{beta} uptake and clearance
Brain, November 1, 2006; 129(11): 3006 - 3019.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
O. Butovsky, M. Koronyo-Hamaoui, G. Kunis, E. Ophir, G. Landa, H. Cohen, and M. Schwartz
From the Cover: Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1
PNAS, August 1, 2006; 103(31): 11784 - 11789.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
P. Lee, L. Medina, and J. M. Ringman
The Thr354Ile substitution in PSEN1:: Disease-causing mutation or polymorphism?
Neurology, June 27, 2006; 66(12): 1955 - 1956.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Kakuda, S. Funamoto, S. Yagishita, M. Takami, S. Osawa, N. Dohmae, and Y. Ihara
Equimolar Production of Amyloid beta-Protein and Amyloid Precursor Protein Intracellular Domain from beta-Carboxyl-terminal Fragment by {gamma}-Secretase
J. Biol. Chem., May 26, 2006; 281(21): 14776 - 14786.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. Koldamova, M. Staufenbiel, and I. Lefterov
Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice
J. Biol. Chem., December 30, 2005; 280(52): 43224 - 43235.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
X. Liang, Q. Wang, T. Hand, L. Wu, R. M. Breyer, T. J. Montine, and K. Andreasson
Deletion of the Prostaglandin E2 EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease
J. Neurosci., November 2, 2005; 25(44): 10180 - 10187.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
J. L. Jankowsky, T. Melnikova, D. J. Fadale, G. M. Xu, H. H. Slunt, V. Gonzales, L. H. Younkin, S. G. Younkin, D. R. Borchelt, and A. V. Savonenko
Environmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer's Disease
J. Neurosci., May 25, 2005; 25(21): 5217 - 5224.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J.-H. Lee, K.-F. Lau, M. S. Perkinton, C. L. Standen, B. Rogelj, A. Falinska, D. M. McLoughlin, and C. C. J. Miller
The Neuronal Adaptor Protein X11{beta} Reduces Amyloid {beta}-Protein Levels and Amyloid Plaque Formation in the Brains of Transgenic Mice
J. Biol. Chem., November 19, 2004; 279(47): 49099 - 49104.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.