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