| Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology. | |
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MedLine Citation:
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PMID: 16574645 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mutations in presenilin 1 (PS1) lead to dominant inheritance of early onset familial Alzheimer disease (FAD). These mutations are known to alter the gamma-secretase cleavage of the amyloid precursor protein, resulting in increased ratio of Abeta42/Abeta40 and accelerated amyloid plaque pathology in transgenic mouse models. To investigate the factors that drive the Abeta42/Abeta40 ratio and amyloid pathogenesis and to investigate the possible interactions between wild-type and FAD mutant PS1, which are co-expressed in transgenic animals, we expressed the PS1 M146V knock-in allele either on wild-type PS1 (PS1M146V/+) or PS1 null (PS1M146V/-) background and crossed these alleles with the Tg2576 APP transgenic mice. Introduction of the PS1 M146V mutation on Tg2576 background resulted in earlier onset of plaque pathology. Surprisingly, removing the wild-type PS1 in the presence of the PS1 M146V mutation (PS1M146V/-) greatly exacerbated the amyloid burden; and this was attributed to a reduction of gamma-secretase activity rather than an increase in Abeta42. Our findings establish a protective role of the wild-type PS1 against the FAD mutation-induced amyloid pathology through a partial loss-of-function mechanism. |
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Authors:
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Runsheng Wang; Baiping Wang; Wanxia He; Hui Zheng |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-03-29 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 281 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2006 Jun |
Date Detail:
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Created Date: 2006-05-29 Completed Date: 2006-08-07 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 15330-6 Citation Subset: IM |
Affiliation:
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Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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genetics,
metabolism,
pathology,
prevention & control* Amyloid / genetics, metabolism* Animals Disease Models, Animal Genes, Dominant Humans Membrane Proteins / genetics*, physiology* Mice Mice, Mutant Strains Mice, Transgenic Mutation* Presenilin-1 |
| Grant Support | |
ID/Acronym/Agency:
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AG20670/AG/NIA NIH HHS; AG21141/AG/NIA NIH HHS; NS40039/NS/NINDS NIH HHS; T32 AG000183/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amyloid; 0/Membrane Proteins; 0/PSEN1 protein, human; 0/Presenilin-1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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