| First Author | Fang F | Year | 2018 |
| Journal | Hum Mol Genet | Volume | 27 |
| Issue | 6 | Pages | 1002-1014 |
| PubMed ID | 29329433 | Mgi Jnum | J:260790 |
| Mgi Id | MGI:6150493 | Doi | 10.1093/hmg/ddy017 |
| Citation | Fang F, et al. (2018) RAGE mediates Abeta accumulation in a mouse model of Alzheimer's disease via modulation of beta- and gamma-secretase activity. Hum Mol Genet 27(6):1002-1014 |
| abstractText | Receptor for Advanced Glycation End products (RAGE) has been implicated in amyloid beta-peptide (Abeta)-induced perturbation relevant to the pathogenesis of Alzheimer''s disease (AD). However, whether and how RAGE regulates Abeta metabolism remains largely unknown. Abeta 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 Abeta formation, we generated mAPP mice with genetic deletion of RAGE (mAPP/RO). These mice displayed reduced cerebral amyloid pathology, inhibited aberrant APP-Abeta 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 Abeta40 and Abeta42 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 3beta (GSK3beta). Finally, RAGE siRNA-mediated gene silencing or DN-RAGE-mediated signaling deficiency in the enriched human APP neuronal cells demonstrated suppression of activation of GSK3beta, accompanied with reduction in Abeta 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 Abeta, at least in part through activation of GSK3beta and p38 MAP kinase. RAGE is a potential therapeutic target to limit aberrant APP-Abeta metabolism in halting progression of AD. |
