Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice
| Autor: | Weiming Xia, Ivan Lieberburg, Peter St. George Hyslop, Dale Schenk, G. Levesque, Thekla S. Diehl, Peter Seubert, Dennis J. Selkoe, Paul E. Fraser, Billie J. Perry, Dora Kholodenko, Kelly Johnson-Wood, Robert Strome, Johanna M. Rommens, Soyeon Kim, Hong Yao, Angela Davis, Ruth Motter, Martin Citron, R. Sherrington, George A. Carlson, David Westaway, Michael K. Lee |
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| Rok vydání: | 1997 |
| Předmět: |
Genetically modified mouse
Amyloid Genetic Vectors Mutant Enzyme-Linked Immunosorbent Assay Mice Transgenic Biology Transfection medicine.disease_cause Hippocampus General Biochemistry Genetics and Molecular Biology Presenilin Cell Line Amyloid beta-Protein Precursor Mice Alzheimer Disease Presenilin-2 mental disorders Presenilin-1 medicine Animals Humans APH-1 Mutation Amyloid beta-Peptides Wild type Brain Membrane Proteins General Medicine medicine.disease Molecular biology Peptide Fragments Alzheimer's disease |
| Zdroj: | Nature Medicine. 3:67-72 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm0197-67 |
| Popis: | 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 beta 42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid beta-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, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta 42 secretion in all mutant clones. Likewise, mutant but not wildtype PS1 transgenic mice showed significant overproduction of A beta 42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta 42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta 42 production, thus promoting cerebral beta-amyloidosis. |
| Databáze: | OpenAIRE |
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