RAGE mediates Aß accumulation in a mouse model of Alzheimer's disease via modulation of ß- and γ-secretase activity.

Receptor for Advanced Glycation End products (RAGE) has been implicated in amyloid ß-peptide (Aß)-induced perturbation relevant to the pathogenesis of Alzheimer's disease (AD). However, whether and how RAGE regulates Aß metabolism remains largely unknown. Aß formation arises from aberrant cleavage of amyloid pre-cursor protein (APP) by ß- and γ-secretase. To investigate whether RAGE modulates ß- and γ-secretase activity potentiating Aß formation, we generated mAPP mice with genetic deletion of RAGE (mAPP/RO). These mice displayed reduced cerebral amyloid pathology, inhibited aberrant APP-Aß metabolism by reducing ß- and γ-secretases activity, and attenuated impairment of learning and memory compared with mAPP mice. Similarly, RAGE signal transduction deficient mAPP mice (mAPP/DN-RAGE) exhibited the reduction in Aß40 and Aß42 production and decreased ß-and γ-secretase activity compared with mAPP mice. Furthermore, RAGE-deficient mAPP brain revealed suppression of activation of p38 MAP kinase and glycogen synthase kinase 3ß (GSK3ß). Finally, RAGE siRNA-mediated gene silencing or DN-RAGE-mediated signaling deficiency in the enriched human APP neuronal cells demonstrated suppression of activation of GSK3ß, accompanied with reduction in Aß levels and decrease in ß- and γ-secretases activity. Our findings highlight that RAGE-dependent signaling pathway regulates ß- and γ-secretase cleavage of APP to generate Aß, at least in part through activation of GSK3ß and p38 MAP kinase. RAGE is a potential therapeutic target to limit aberrant APP-Aß metabolism in halting progression of AD.