AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation.
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.
Guglielmotto
Michela
M
Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy.
Aragno
Manuela
M
Tamagno
Elena
E
Vercellinatto
Ilenia
I
Visentin
Sonia
S
Medana
Claudio
C
Catalano
Maria Graziella
MG
Smith
Mark A
MA
Perry
George
G
Danni
Oliviero
O
Boccuzzi
Giuseppe
G
Tabaton
Massimo
M
D000544:Alzheimer Disease / Q000209:etiology; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental; D017127:Glycation End Products, Advanced / Q000502:physiology*; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat