Nature Medicine
3, 67 - 72 (1997)
doi:10.1038/nm0197-67
Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid  -protein in both transfected cells and transgenic miceMartin Citron1,6, David Westaway2, Weiming Xia1, George Carlson3, Thekla Diehl1, Georges Levesque2, Kelly Johnson-wood4, Michael Lee4, Peter Seubert4, Angela Davis3, Dora Kholodenko4, Ruth Motter4, Robin Sherrington2, Billie Perry3, Hong Yao2, Robert Strome2, Ivan Lieberburg4, Johanna Rommens2, Soyeon Kim5, Dale Schenk4, Paul Fraser2, Peter St George Hyslop2
& Dennis J. Selkoe1,6
1Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115, USA
2Centre for Research into Neurodegenerative Disease, Departments of Medicine (Neurology), Medical Biophysics, Medical and Molecular Genetics and Pathology, University of Toronto, 6 Queen's Park Crescent, Toronto, Ontario, Canada M5S 1A8
3McLauglin Research Institute, 1520 23rd Street South, Great Falls, Montana 59409, USA
4Athena Neurosciences Inc., 800F Gateway Boulevard, South San Francisco, California 94080, USA
5Department ofBiostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA
6Correspondence should be addressed to M.C. or D.J.S. The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A 42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid -protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels,  - and -secretase activity and A production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A42 secretion in all mutant clones. Likewise, mutant but not wild-type PS1 transgenic mice showed significant overproduction of A42 in the brain, and this effect was detectable as early as 2−4 months of age. Different PS mutations had differential effects on A generation. The extent of A42 increase did not correlate with presenilin expression levels. Our data demonstrate that the preseniiin mutations cause a dominant gain of function and may induce AD by enhancing A42 production, thus promoting cerebral -amyloidosis.
REFERENCES
- Selkoe, D.J., Amyloid
 -protein and the genetics of Alzheimer's disease. J. Biol. Chem. 271, 18295−18296 (1996). | PubMed | ISI | ChemPort |
- Jarrett, J.T., Berger, E.P. & Lansbury, P.T., The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693−4697 (1993). | PubMed | ISI | ChemPort |
- Scheuner, D. et al. Secreted amyloid -protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med. 2, 864−870 (1996). | Article | PubMed | ISI | ChemPort |
- Yankner, B.A. New clues to Alzheimer's disease: Unraveling the roles of amyloid and tau. Nature Med. 2, 850−852 (1996). | Article | PubMed | ISI | ChemPort |
- Citron, M. et al. Inhibition of amyloid -protein production in neural cells by the serine protease inhibitor AEBSF. Neuron 17, 171−179 (1996). | Article | PubMed | ISI | ChemPort |
- Citron, M., Teplow, D.B. & Selkoe, D.J. Generation of amyloid -protein from its precursor is sequence specific. Neuron 14, 661−670 (1995). | PubMed | ISI | ChemPort |
- Knops, J. et al. Cell-type and amyloid precursor protein-type specific inhibition of A release by Bafilomycin A1, a selective inhibitor of vacuolar ATPases. J. Biol. Chem. 270, 2419−2422 (1995). | Article | PubMed | ISI | ChemPort |
- Haass, C. et al. The Swedish mutation causes early-onset Alzheimer's disease by -secretase cleavage within the secretory pathway. Nature Med. 1, 1291−1296 (1995). | Article | PubMed | ISI | ChemPort |
- Thinakaran, G. et al. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181−190 (1996). | Article | PubMed | ISI | ChemPort |
- Walter, J. et al. The Alzheimer's disease associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol. Med. (in the press).
- Podlisny, M.B., Tolan, D. & Selkoe, D.J. Homology of the amyloid -protein precursor in monkey and human supports a primate model for -amyloidosis in Alzheimer's disease. Am. J. Pathol. 138, 1423−1435 (1991). | PubMed | ISI | ChemPort |
- Haass, C., Hung, A.Y., Selkoe, D.J. & Teplow, D.B. Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid -protein precursor. J. Biol. Chem. 269, 17741−17748 (1994). | PubMed | ISI | ChemPort |
- Haass, C. et al. Amyloid -peptide is produced by cultured cells during normal metabolism. Nature 359, 322−325 (1992). | Article | PubMed | ISI | ChemPort |
- Citron, M. et al. Evidence that A42 and A40 are generated from the -amyloid precursor protein by different protease activities. Proc. Natl. Acad. Sci. USA 93, 13170−13175 (1996). | Article | PubMed | ChemPort |
- Scott, M.R., Kohler, R., Foster, D. & Prusiner, S.B. Chimeric prion protein expression in cultured cells and transgenic mice. Protein Sci. 1, 986−997 (1992). | PubMed | ISI | ChemPort |
- Prusiner, S., Scott, M., Foster, D., Westaway, D. & DeArmond, S. Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63, 673−686 (1990). | Article | PubMed | ISI | ChemPort |
- Moser, M., Colello, R.J., Pott, U. & Oesch, B. Developmental expression of the PrP gene in glial cells. Neuron 14, 509−517 (1995). | PubMed | ISI | ChemPort |
- Hsiao, K.K. et al. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15, 1203−1218 (1995). | Article | PubMed | ISI | ChemPort |
- Sherrington, R. et al. Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer disease. Nature 375, 754−760 (1995). | Article | PubMed | ISI | ChemPort |
- Rogaev, E.I. et al. Analysis of the 5' sequence, genomic structure and alternative splicing of the presenilin 1 gene associated with early onset Alzheimer's disease. Genomics (in the press).
- Foncin, J.F. et al. Alzheimer's presenile dementia transmitted in an extended kindred. Rev. Neurol. (Paris) 141, 194−202 (1985). | PubMed | ChemPort |
- Frommelt, P., Schnabel, R., Kuhne, W., Nee, L.E. & Polinsky, R.J., Alzheimer disease: A large multigenerational German kindred. Alzheimer Dis. Assoc. Disorders 5, 36−43 (1991). | ISI | ChemPort |
- Seubert, P. et al. Secretion of -amyloid precursor protein cleaved at the amino-terminus of the -amyloid peptide. Nature 361, 260−263 (1993). | Article | PubMed | ISI | ChemPort |
- Radzicka, A. & Wolfenden, R. Comparing the polarities of the amino acids: Side-chain distribution coefficients between the vapor phase, cyclohexane, 1-octanol, and neutral aqueous solution. Biochemistry 27, 1664−1670 (1988). | ISI | ChemPort |
- Sherrington, R. et al. Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum. Mol. Genetics 5, 985−988 (1996). | Article | ISI | ChemPort |
- Lemere, C.A. et al. The E280A presenilin 1 Alzheimer mutation produces increased Ap42 deposition and severe cerebellar pathology. Nature Med. 2, 1146−1150 (1996). | Article | PubMed | ISI | ChemPort |
- Rogaev, E.I. et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376, 775−778 (1995). | Article | PubMed | ISI | ChemPort |
- Seubert, P. et al. Isolation and quantitation of soluble Alzheimer's -peptide from biological fluids. Nature 359, 325−327 (1992). | Article | PubMed | ISI | ChemPort |
|
