Supplementary Material for: RAGE Does Not Affect Amyloid Pathology in Transgenic ArcAβ Mice

Background: Alzheimer’s disease (AD) is characterized by brain accumulation of the amyloid-β peptide (Aβ) that triggers a cascade of biochemical and cellular alterations resulting in the clinical phenotype of the disease. While numerous experiments addressed Aβ toxicity, the mechanisms are still not fully understood. The receptor for advanced glycation end products (RAGE) binds Aβ and was suggested to be involved in the pathological processes of AD. Objective: Our purpose was to assess the effect of RAGE deletion on Aβ-related pathology. Methods: We crossed RAGE knockout (RAGE–/–) mice with transgenic mice harboring both the Swedish and Arctic Aβ precursor protein mutations (arcAβ mice). We assessed Aβ levels, Aβ brain deposition, Aβ-degrading enzyme activities, Aβ precursor protein expression and processing, number and morphology of microglia as well as cognitive performance of 6- and 12-month-old RAGE–/–/arcAβ, RAGE–/–, arcAβ and wild-type mice. Results: RAGE–/–/arcAβ mice had significantly lower levels of SDS- and formic-acid-extracted Aβ 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 Aβ peptide. Furthermore, histological analysis revealed no difference in the microglia-occupied brain areas or microglial morphologies between RAGE–/–/arcAβ and arcAβ 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, Aβ accumulation and microglial activation in the arcAβ mouse model of AD.