Cell cycle related signaling in Neuro2a cells proceeds via the receptor for advanced glycation end products.
Re-expression of cell cycle related genes such as cyclin-dependent kinases (cdk), cyclins, or cdk inhibitors in differentiated neurons in Alzheimer's disease (AD) is rooted in aberrant mitogenic signaling. Since microglia and astroglia proliferate in the vicinity of amyloid plaques, it is likely that plaque components or factors secreted from plaque-activated glia induce mitogenic signaling in neurons. Mitogenic compounds might be S100B, overexpressed by activated astrocytes, or advanced glycation end products (AGEs), a component of plaques. Both S100B and AGEs may interact with the multiligand receptor for AGEs (RAGE) and trigger for the activation of the p42/44 mitogen-activated protein kinase (p42/44 MAPK), whether they also count for cell cycle related signaling in neurons remains unresolved. By immunohistochemical staining, we confirmed that cyclin D(1) positive neurons are surrounded by AGE deposits, demonstrating the potential relevance in vivo. For exploring the mitogenic signal cascade, we used Neuro2a cells overexpressing human full-length RAGE (FL-RAGE) or the cytosolic deletion mutant (Delta-RAGE). In both cell lines, S100B and AGEs induced the production of reactive oxygen species but not in a RAGE-dependent manner. By contrast, in FL-RAGE cells but not in Delta-RAGE cells S100B and AGEs activate p42/44 MAPK, augment cyclin D(1)/cdk4 protein and RNA levels and the transition into the S-phase. Moreover, in FL-RAGE cells, decreased protein levels of the cdk inhibitor p16 were observed, and the p42/44 MAPK inhibitor UO126 prevented AGE and S100B stimulated cyclin D(1) expression and hindered cells to enter the S-phase. Our results demonstrate that S100B and AGE may serve as mitogenic sources for the stimulation of neurons to progress through the cell cycle whereby signaling proceeds via RAGE --> p42/44 MAPK --> cyclin D(1)/cdk4.
Schmidt
A
A
Department of Neuroanatomy, Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig, Germany.
Kuhla
B
B
Bigl
K
K
Münch
G
G
Arendt
T
T
D000368:Aged; D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D019942:Genes, p16 / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D010766:Phosphorylation; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000032:analysis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019938:Cyclin D1; D012313:RNA; D004247:DNA; D051358:Cyclin-Dependent Kinase 4; D019950:Mitogen-Activated Protein Kinase 1