Reduced brain volumes in mice expressing APP-Austrian mutation but not in mice expressing APP-Swedish-Austrian mutations.
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.
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
Bianca
B
Van Broeck
Greet
G
Vanhoutte
Ivy
I
Cuijt
Sandra
S
Pereson
Geert
G
Joris
Jean-Pierre
JP
Timmermans
Annemie
A
Van der Linden
Christine
C
Van Broeckhoven
Samir
S
Kumar-Singh
D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000145:classification* / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)