Article: Reduced brain volumes in mice expressing APP-Austrian mutation but not in mice expressing APP-Swedish-Austrian mutations.
2008 Volume 447, Issue 2-3, Page(s) 143–147
Abstract: We previously described two transgenic mouse lines expressing sub-endogenous levels of the 'Austrian' APP-T714I mutation (driven by the prenatally active PDGF-beta promoter; APP-Au mice) and showing intraneuronal Abeta pathology and reduced brain volumes ...
Abstract | We previously described two transgenic mouse lines expressing sub-endogenous levels of the 'Austrian' APP-T714I mutation (driven by the prenatally active PDGF-beta promoter; APP-Au mice) and showing intraneuronal Abeta pathology and reduced brain volumes on MRI at 12 and 20 months of age. To further investigate whether reduced brain sizes were caused by neurodegeneration or a neurodevelopmental defect, we now measured brain volumes as early as postnatal day 10. At this age, a distinguishable reduction in brain volumes was absent, indicating that brain volume deficits in APP-Au mice are not caused by a neurodevelopmental defect. To further study the association between intraneuronal Abeta and reduced brain volumes, we further generated and analyzed an APP transgenic mouse model expressing both Austrian and Swedish (K670N/M671L) mutations (APP-SwAu mice). APP-Swedish mutation is known to lead to altered APP processing in the secretory pathway, precluding its later processing in endosomal-lysosomal compartments, the site of intraneuronal Abeta accumulation. Also, to have higher levels of transgene expression only after birth, a murine Thy-1 promoter was utilized for APP-SwAu mouse lines. Despite having five times higher transgene APP levels compared to APP-Au mice, APP-SwAu mice showed significantly lower intraneuronal Abeta levels in the absence of reduced brain volumes, suggesting that intraneuronal Abeta accumulation is related to reduced brain volumes in APP-Au mice. These data also provide a first in vivo indication of altered processing of APP-Swedish at sub-endogenous levels, an effect not observed in mouse models expressing the APP-Swedish mutation in high amounts. |
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MeSH term(s) | Age Factors ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/classification ; Amyloid beta-Protein Precursor/genetics ; Analysis of Variance ; Animals ; Brain/pathology ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay/methods ; Humans ; Mice ; Mice, Transgenic ; Mutation/genetics ; Peptide Fragments/genetics ; Peptide Fragments/metabolism |
Chemical Substances | Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Peptide Fragments ; amyloid beta-protein (1-40) ; amyloid beta-protein (1-42) |
Language | English |
Publishing date | 2008-12-12 |
Publishing country | Ireland |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 194929-9 |
ISSN | 1872-7972 ; 0304-3940 |
ISSN (online) | 1872-7972 |
ISSN | 0304-3940 |
DOI | 10.1016/j.neulet.2008.09.073 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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