Human Molecular Genetics Advance Access originally published online on November 25, 2003
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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 
secretase
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 
-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 -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 -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 -secretase, but rather that they have more complex effects on the regulation of -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
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