AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation

NEUROBIOLOGY OF AGING

卷:33

Article

Guglielmotto, Michela¹  Aragno, Manuela¹  Tamagno, Elena^1,2  Vercellinatto, Ilenia¹  Visentin, Sonia³  Medana, Claudio³  Catalano, Maria Graziella⁴  Smith, Mark A.⁵  Perry, George⁶  Danni, Oliviero¹  Boccuzzi, Giuseppe⁴  Tabaton, Massimo⁷ 

[1] Univ Turin, Dept Expt Med & Oncol, I-10125 Turin, Italy

[2] Cavalieri Ottolenghi Fdn, Inst Sci, Turin, Italy

[3] Univ Turin, Dept Analyt Chem, I-10125 Turin, Italy

[4] Univ Turin, Dept Clin Pathophysiol, I-10125 Turin, Italy

[5] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA

[6] Univ Texas San Antonio, Coll Sci, San Antonio, TX USA

[7] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy

关键词: Advanced glycation end products;    RAGE;    BACE1;    Alzheimer disease;    Diabetes;    NF-kappa B pathway;   

DOI  :  10.1016/j.neurobiolaging.2010.05.026

来源: Elsevier

【 摘 要 】

Although the pathogenesis of sporadic Alzheimer disease (AD) is not clearly understood, it is likely dependent on several age-related factors. Diabetes is a risk factor for AD, and multiple mechanisms connecting the 2 diseases have been proposed. Hyperglycemia enhances the formation of advanced glycation end products (AGEs) that result from the auto-oxidation of glucose and fructose. The interaction of AGEs with their receptor, named RAGE, elicits the formation of reactive oxygen species that are also believed to be an early event in AD pathology. To investigate a functional link between the disorders diabetes and AD, the effect of 2 AGEs, pentosidine and glyceraldehydes-derived pyridinium (GLAP), was studied on BACE1 expression both in vivo, in streptozotocin treated rats, and in vitro in differentiated neuroblastoma cells. We showed that pentosidine and GLAP were able to upregulate BACE1 expression through their binding with RAGE and the consequent activation of NF-kappa B. In addition, both pentosidine and GLAP were found to be increased in the brain in sporadic AD patients. Our findings demonstrate that activation of the AGEs/RAGE axis, by upregulating the key enzyme for amyloid-beta production, provides a pathologic link between diabetes mellitus and AD. (C) 2012 Elsevier Inc. All rights reserved.

【 授权许可】

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