Signal transduction pathways in mouse microglia N‐11 cells activated by advanced glycation endproducts (AGEs)

Abstract

Deposition of cross-linked insoluble protein aggregates such as amyloid plaques is characteristic for Alzheimer's disease. Microglial activation by these extracullar deposits has been proposed to play a crucial role in functional degeneration as well as cell death of neurones. A sugar-derived post-translational modification of long-lived proteins, advanced glycation endproducts (AGEs), activate specific signal transduction pathways, resulting in the up-regulation of various proinflammatory signals such as cytokines [interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-a)] and inducible nitric oxide synthase (iNOS). Our goal was to study AGE-activated signal transduction pathways involved in the induction of proinflammatory effectors in the murine microglial cell line N-11. Chicken egg albumin-AGE (CEA-AGE), used as model AGE, induces nitric oxide (NO), TNF-a and IL-6 production. The AGE receptor, RAGE, and the transcription factor, nuclear factor kappa B (NF-jB), appear to be involved in all pathways, since a neutralizing RAGE antibody and a peptide inhibiting NF-jB translocation down-regulated NO, TNF-a and IL-6 production. NO and TNF-a, but not IL-6 production appear to be regulated independently, since NOS inhibitors did not decrease TNF-a secretion and a neutralizing TNF-a antibody did not reduce NO production, while employment of NOS inhibitors reduced significantly the secretion of IL-6. Inhibition of the MAP-kinase-kinase (MEK) and phosphatidylinositol 3-kinase (PI 3 K) pathway, but not that of mitogen-activated protein kinase-p38 (MAPK-p38), reduced NO, TNF-a and IL-6 significantly, suggesting that simultaneous activation of the first two pathways is necessary for the AGE-induced induction of these pro-inflammatory stimuli.

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

“…In this study, we identified the role of RAGE in A␤-induced brain endothelial CCR5 expression. RAGE is a member of the Ig superfamily of cell surface molecules with a diverse repertoire of ligands, including advanced glycation end products, S100 proteins, amphoterin, A␤ peptide, ␤-sheet fibrils, and the leukocyte ␤ 2 -integrin MAC-1 (39,42). In the brain, RAGE is normally expressed by endothelial cells, microglia, and neurons at low levels.…”

“…Many studies suggest that RAGE may play an important role in the regulation of inflammation (39,42,43,66). Through RAGE, some ligands can bind to mononuclear phagocytes and modify their functions, including expression of key inflammatory mediators (67)(68)(69)(70).…”

“…Additional studies suggested that ERK and JNK are downstream signal molecules coupled to RAGE (39). There are also reports about involvement of PI3K in intracellular RAGE signaling (42,43). Therefore, we tried to explore whether RAGE is involved in A␤-dependent CCR5 expression in HBMECs.…”

“…It is well documented that sRAGE is cleaved from cell surface RAGE by matrix metalloproteinase, which is the extracellular ligand-binding domain of RAGE. sRAGE binds with ligands of RAGE to block their interaction with and activation of RAGE (39,42). To corroborate the role of RAGE in A␤-primed T cell TEM in AD, rat sRAGE was expressed and purified (Fig.…”

Views From Within and Beyond: Narratives of Cardiac Contractile Dysfunction Under Senescence

“…Accumulation of AGEs during the aging process occurs in long-lived proteins, such as collagens, lens crystalline, and cartilage. Therefore, AGE in essence is a sugar-derived post-translational modification of functional proteins (113). AGE deposits have been immunolocalized in skin, lung, kidney, intestine, intervertebral disks, as well as in heart and arteries of aged and diabetic patients (114).…”