| The Psen1-L166P-knock-in mutation leads to amyloid deposition in human wild-type amyloid precursor protein YAC transgenic mice. | |
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MedLine Citation:
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PMID: 22459153 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Genetically engineered mice have been generated to model cerebral β-amyloidosis, one of the hallmarks of Alzheimer disease (AD) pathology, based on the overexpression of a mutated cDNA of the amyloid-β precursor protein (AβPP) or by knock-in of the murine Aβpp gene alone or with presenilin1 mutations. Here we describe the generation and initial characterization of a new mouse line based on the presence of 2 copies of the human genomic region encoding the wild-type AβPP and the L166P presenilin 1 mutation. At ∼6 mo of age, double-mutant mice develop amyloid pathology, with signs of neuritic dystrophy, intracellular Aβ accumulation, and glial inflammation, an increase in AβPP C-terminal fragments, and an 8 times increase in Aβ42 levels with a 40% decrease in Aβ40 levels, leading to a significant increase (14 times) of Aβ42/Aβ40 ratios, with minimal effects on presenilin or the Notch1 pathway in the brain. We conclude that in mice, neither mutations in AβPP nor overexpression of an AβPP isoform are a prerequisite for Aβ pathology. This model will allow the study of AD pathogenesis and testing of therapeutic strategies in a more relevant environment without experimental artifacts due to the overexpression of a single-mutant AβPP isoform using exogenous promoters. |
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Authors:
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Ruben Vidal; Neeraja Sammeta; Holly J Garringer; Kumar Sambamurti; Leticia Miravalle; Bruce T Lamb; Bernardino Ghetti |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-03-29 |
Journal Detail:
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Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 26 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2012 Jul |
Date Detail:
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Created Date: 2012-06-29 Completed Date: 2012-09-20 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 2899-910 Citation Subset: IM |
Affiliation:
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Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. rvidal@iupui.edu |
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 Amino Acid Substitution Amyloid beta-Protein Precursor / genetics*, metabolism* Amyloidogenic Proteins / metabolism* Animals Base Sequence Brain / metabolism, pathology Chromosomes, Artificial, Yeast / genetics DNA, Complementary / genetics Disease Models, Animal Female Gene Knock-In Techniques Humans Male Mice Mice, Inbred C57BL Mice, Mutant Strains Mice, Transgenic Mutant Proteins / genetics*, metabolism* Presenilin-1 / genetics*, metabolism* Receptors, Notch / metabolism Recombinant Proteins / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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AG037338/AG/NIA NIH HHS; AG10133/AG/NIA NIH HHS; NS050227/NS/NINDS NIH HHS; NS14426/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein Precursor; 0/Amyloidogenic Proteins; 0/DNA, Complementary; 0/Mutant Proteins; 0/PSEN1 protein, human; 0/Presenilin-1; 0/Receptors, Notch; 0/Recombinant Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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