Microglial Cell Death Induced by Glycated Bovine Serum Albumin: Nitric Oxide Involvement

Abstract

Nonenzymatic glycation results in the formation of advanced glycation end products (AGEs) through a nonenzymatic multistep reaction of reducing sugars with proteins. AGEs have been suspected to be involved in the pathogenesis of several chronic clinical neurodegenerative complications including Alzheimer's disease, which is characterized with the activation of microglial cells in neuritic plaques. To find out the consequence of this activation on microglial cells, we treated the cultured microglial cells with different glycation levels of Bovine Serum Albumin (BSA) which were prepared in vitro. Extent of glycation of protein has been characterized during 16 weeks of incubation with glucose. Treatment of microglial cells with various levels of glycated albumin induced nitric oxide (NO) production and consequently cell death. We also tried to find out the mode of death in AGE-activated microglial cells. Altogether, our results suggest that AGE treatment causes microglia to undergo NO-mediated apoptotic and necrotic cell death in short term and long term, respectively. NO production is a consequence of iNOS expression in a JNK dependent RAGE signalling after activation of RAGE by AGE-BSA.

Nicotine Reduces the Cytotoxic Effect of Glycated Proteins on Microglial Cells

“…2). In support of our results from cell viability study, the glycated-BSA samples, in which the b-sheet content was higher [9], induced more NO production in microglial cells, indicating that they can activate RAGE receptor better than proteins that acquired more glycation but did not adopted enough b-sheet content (Fig. 4c).…”

“…Microglial viability stands for the activation of RAGE signaling. The binding of glycated proteins to RAGE on microglial cells results in activation of microglial cells and NO production and finally programmed cell death [9]. To be sure that RAGE is also expressed in our primary microglial preparations, we analyzed the expression of RAGE in cultured cells by Western blotting.…”

“…These amyloid structures are recognized by the receptor of AGE (RAGE) on the surface of several cell types, and binding induces different signal transduction pathways inside these cells [9,10].…”

“…Binding of b-sheeted AGE-proteins to RAGEs on microglial cells can also induce the same signaling pathways and potentially can lead to AD [9,14,15].…”

Platelet Aggregation Increased by Advanced Glycated Hemoglobin

“…The chemistry of AGEs is not fully understood; in the meantime increased levels of circulating AGEs have been demonstrated in both animal and human diabetics [9]. AGE structures are associated with many pathophysiological abnormalities [10] as in diabetes and aging [11,12].…”