Human Molecular Genetics Advance Access published online on November 25, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddh019
© 2003 by Oxford University Press
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1 Departments of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Ave., Baltimore, MD 21205
* To whom correspondence should be addressed. E-mail: drbor{at}jhmi.edu.
Amyloid precursor protein [APP] is endoproteolytically processed by BACE1 and
Article
Mutant presenilins specifically elevate the levels of the 42 residue
-amyloid peptide in vivo: Evidence for augmentation of a 42-specific gamma secretase
2 Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville FL 32224
3 Merck Research Labs, San Diego, 505 Coast Boulevard South, La Jolla, CA 92037
4 Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702
5 Merck Research Labs, San Diego, 505 Coast Boulevard South, La Jolla, CA 92037; Neurogenetics Inc., 11085 North Torrey Pines Road, Suite 300, La Jolla, CA 92037
6 Departments of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Ave., Baltimore, MD 21205; Neuroscience, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Ave., Baltimore, MD 21205
Abstract 
-secretase to release amyloid peptides [A
40 and 42] that aggregate to form senile plaques in the brains of patients with Alzheimer's disease [AD]. The C-terminus of A40/42 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 A40:42 to favor A42. One hypothesis to explain this outcome is that mutant PS alters the specificity of -secretase to favor production of A42 at the expense of A40. To test this hypothesis in vivo, we studied A40 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 A42 and the rate of amyloid deposition. We further show that the shift in A42:40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady state levels of A42, while maintaining a constant level of A40. 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.
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