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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
1997-1-31
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1078-8956
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pubmed:author |
pubmed-author:CarlsonGG,
pubmed-author:CitronMM,
pubmed-author:DavisAA,
pubmed-author:DiehlTT,
pubmed-author:FraserPP,
pubmed-author:Johnson-WoodKK,
pubmed-author:KholodenkoDD,
pubmed-author:KimSS,
pubmed-author:LeaII,
pubmed-author:LevesqueGG,
pubmed-author:LieberburgII,
pubmed-author:MottesMM,
pubmed-author:PerryBB,
pubmed-author:RommensJJ,
pubmed-author:SchenkDD,
pubmed-author:SelkoeD JDJ,
pubmed-author:SeubertPP,
pubmed-author:SherringtonRR,
pubmed-author:St George HyslopPP,
pubmed-author:StromeRR,
pubmed-author:WestawayDD,
pubmed-author:XieSS,
pubmed-author:YaoHH
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pubmed:issnType |
Print
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pubmed:volume |
3
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
67-72
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:8986743-Alzheimer Disease,
pubmed-meshheading:8986743-Amyloid beta-Peptides,
pubmed-meshheading:8986743-Amyloid beta-Protein Precursor,
pubmed-meshheading:8986743-Animals,
pubmed-meshheading:8986743-Brain,
pubmed-meshheading:8986743-Cell Line,
pubmed-meshheading:8986743-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:8986743-Genetic Vectors,
pubmed-meshheading:8986743-Hippocampus,
pubmed-meshheading:8986743-Humans,
pubmed-meshheading:8986743-Membrane Proteins,
pubmed-meshheading:8986743-Mice,
pubmed-meshheading:8986743-Mice, Transgenic,
pubmed-meshheading:8986743-Mutation,
pubmed-meshheading:8986743-Peptide Fragments,
pubmed-meshheading:8986743-Presenilin-1,
pubmed-meshheading:8986743-Presenilin-2,
pubmed-meshheading:8986743-Transfection
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pubmed:year |
1997
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pubmed:articleTitle |
Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice.
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pubmed:affiliation |
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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