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

Topic: Brain proteins, microglia and lab models

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-κB. 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-β production, provides a pathologic link between diabetes mellitus and AD.

Key findings

• Hyperglycemia enhances the formation of advanced glycation end products (AGEs) that result from the auto-oxidation of glucose and fructose.
• We showed that pentosidine and GLAP were able to upregulate BACE1 expression through their binding with RAGE and the consequent activation of NF-κB.
• Our findings demonstrate that activation of the AGEs/RAGE axis, by upregulating the key enzyme for amyloid-β production, provides a pathologic link between diabetes mellitus and AD.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.neurobiolaging.2010.05.026
• PubMed: 20638753
• Original source →

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@article{guglielmotto2012-20638753,
  author  = {Guglielmotto, M. and Aragno, M. and Tamagno, E. and Vercellinatto, I. and Visentin, S. and Medana, C. and Catalano, M. G. and Smith, M. A. and others},
  title   = {{AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation}},
  journal = {Neurobiology of aging},
  year    = {2012},
  doi     = {10.1016/j.neurobiolaging.2010.05.026},
  pmid    = {20638753},
  url     = {https://doi.org/10.1016/j.neurobiolaging.2010.05.026}
}

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