Document Detail


The Psen1-L166P-knock-in mutation leads to amyloid deposition in human wild-type amyloid precursor protein YAC transgenic mice.
MedLine Citation:
PMID:  22459153     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Ruben Vidal; Neeraja Sammeta; Holly J Garringer; Kumar Sambamurti; Leticia Miravalle; Bruce T Lamb; Bernardino Ghetti
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-03-29
Journal Detail:
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:
Created Date:  2012-06-29     Completed Date:  2012-09-20     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2899-910     Citation Subset:  IM    
Affiliation:
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. rvidal@iupui.edu
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / 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:
AG037338/AG/NIA NIH HHS; AG10133/AG/NIA NIH HHS; NS050227/NS/NINDS NIH HHS; NS14426/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
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
Comments/Corrections

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