title: Advanced glycation end products are mitogenic signals and trigger cell cycle reentry of neurons in Alzheimer's disease brain.
abstract: Neurons that reenter the cell cycle die rather than divide, a phenomenon that is associated with neurodegeneration in Alzheimer's disease (AD). Reexpression of cell-cycle related genes in differentiated neurons in AD might be rooted in aberrant mitogenic signaling. Because microglia and astroglia proliferate in the vicinity of amyloid plaques, it is likely that plaque components or factors secreted from plaque-activated glia induce neuronal mitogenic signaling. Advanced glycation end products (AGEs), protein-bound oxidation products of sugar, might be one of those mitogenic compounds. Cyclin D1 positive neurons are colocalized with AGEs or directly surrounded by extracellular AGE deposits in AD brain. However, a direct proof of DNA replication in these cells has been missing. Here, we report by using fluorescent in situ hybridization that consistent with the expression of cell cycle proteins, hyperploid neuronal cells are in colocalization with AGE staining in AD brains but not in nondemented controls. To complement human data, we used apolipoprotein E-deficient mice as model of neurodegeneration and showed that increased oxidative stress caused an intensified neuronal deposition of AGEs, being accompanied by an activation of the MAPK cascade via RAGE. This cascade, in turn, induced the expression of cyclin D1 and DNA replication. In addition, reduction of oxidative stress by application of α-lipoic acid decreased AGE accumulations, and this decrease was accompanied by a reduction in cell cycle reentry and a more euploid neuronal genome.
authors.affiliation: Institute for Experimental Surgery, Medical School Rostock, University of Rostock, Rostock, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Kuhla
authors.affiliation: Institute for Experimental Surgery, Medical School Rostock, University of Rostock, Rostock, Germany.
authors.forename: Sophie C
authors.initials: SC
authors.lastname: Ludwig
authors.affiliation: Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany. Electronic address: b.kuhla@fbn-dummerstorf.de.
authors.forename: Björn
authors.initials: B
authors.lastname: Kuhla
authors.affiliation: Department of Pharmacology, School of Medicine, University of Western Sydney, Penrith, New South Wales, Australia.
authors.forename: Gerald
authors.initials: G
authors.lastname: Münch
authors.affiliation: Institute for Experimental Surgery, Medical School Rostock, University of Rostock, Rostock, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000166:cytology / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction; D008063:Thioctic Acid / Q000494:pharmacology
chemical_list: C530105:Ccnd1 protein, mouse; D017127:Glycation End Products, Advanced; D019938:Cyclin D1; D008063:Thioctic Acid; C498977:Mok protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: Advanced glycation end products; Alzheimer's disease; Cell cycle reentry; Mitogenic signaling