RAGE does not affect amyloid pathology in transgenic ArcAbeta mice.
BACKGROUND
Alzheimer's disease (AD) is characterized by brain accumulation of the amyloid-beta peptide (Abeta) that triggers a cascade of biochemical and cellular alterations resulting in the clinical phenotype of the disease. While numerous experiments addressed Abeta toxicity, the mechanisms are still not fully understood. The receptor for advanced glycation end products (RAGE) binds Abeta and was suggested to be involved in the pathological processes of AD.


OBJECTIVE
Our purpose was to assess the effect of RAGE deletion on Abeta-related pathology.


METHODS
We crossed RAGE knockout (RAGE(-/-)) mice with transgenic mice harboring both the Swedish and Arctic Abeta precursor protein mutations (arcAbeta mice). We assessed Abeta levels, Abeta brain deposition, Abeta-degrading enzyme activities, Abeta precursor protein expression and processing, number and morphology of microglia as well as cognitive performance of 6- and 12-month-old RAGE(-/-)/arcAbeta, RAGE(-/-), arcAbeta and wild-type mice.


RESULTS
RAGE(-/-)/arcAbeta mice had significantly lower levels of SDS- and formic-acid-extracted Abeta in the cortex and hippocampus, with concomitantly increased activity of insulin-degrading enzyme at the age of 6 months. However, RAGE deletion could neither prevent the decline in cognitive performance nor the age-related cerebral accumulation of Abeta peptide. Furthermore, histological analysis revealed no difference in the microglia-occupied brain areas or microglial morphologies between RAGE(-/-)/arcAbeta and arcAbeta mice.


CONCLUSIONS
Together, our results indicate that while the absence of RAGE was associated with increased insulin-degrading enzyme activity in the brain, it was not sufficient to prevent or ameliorate cognitive deterioration, Abeta accumulation and microglial activation in the arcAbeta mouse model of AD.
Division of Psychiatry Research, University of Zurich, CH-8008 Zurich, Switzerland. ivana.vodopivec @ bli.uzh.ch
Ivana
I
Vodopivec
Arnaud
A
Galichet
Marlen
M
Knobloch
Angelika
A
Bierhaus
Claus W
CW
Heizmann
Roger M
RM
Nitsch
D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D013223:Statistics as Topic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)