RAGE mediates Aβ accumulation in a mouse model of Alzheimer's disease via modulation of β- and γ-secretase activity

Receptor for Advanced Glycation End products (RAGE) has been implicated in amyloid beta-peptide (A beta)-induced perturbation relevant to the pathogenesis of Alzheimer's disease (AD). However, whether and how RAGE regulates A beta metabolism remains largely unknown. A beta formation arises from aberrant cleavage of amyloid pre-cursor protein (APP) by beta- and gamma-secretase. To investigate whether RAGE modulates beta- and gamma-secretase activity potentiating A beta formation, we generated mAPP mice with genetic deletion of RAGE (mAPP/RO). These mice displayed reduced cerebral amyloid pathology, inhibited aberrant APP-A beta metabolism by reducing beta- and gamma-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 A beta 40 and A beta 42 production and decreased beta-and gamma-secretase activity compared with mAPP mice. Furthermore, RAGE-deficient mAPP brain revealed suppression of activation of p38 MAP kinase and glycogen synthase kinase 3 beta (GSK3 beta). Finally, RAGE siRNA-mediated gene silencing or DN-RAGE-mediated signaling deficiency in the enriched human APP neuronal cells demonstrated suppression of activation of GSK3 beta, accompanied with reduction in A beta levels and decrease in beta- and gamma-secretases activity. Our findings highlight that RAGE-dependent signaling pathway regulates beta- and gamma-secretase cleavage of APP to generate A beta, at least in part through activation of GSK3 beta and p38 MAP kinase. RAGE is a potential therapeutic target to limit aberrant APP-A beta metabolism in halting progression of AD.