Altered intracellular signaling and reduced viability of Alzheimer's disease neuronal cybrids is reproduced by beta-amyloid peptide acting through receptor for advanced glycation end products (RAGE).
Activation of apoptosis by increased production of amyloid beta peptides (Abeta) has been implicated in neuronal cell death of Alzheimer's disease (AD). We used mitochondrial transgenic cybrid models of sporadic AD (SAD), which overproduce Abeta compared to control (CTL) cybrids, to investigate the effects of endogenously generated Abeta on intracellular signaling pathways and viability. Reducing SAD Abeta production with gamma-secretase inhibition altered the total phosphorylation profile of SAD cybrid to one similar to CTL cybrids and enhanced viability to approximately CTL cybrid levels. Treating CTL cybrids with exogenous Abeta or conditioned media (CM) from SAD cybrids activated the signaling pathways active in SAD cybrids under basal condition and decreased viability. Antibodies against receptor for advanced glycation end products (RAGE) blocked Abeta-induced activation of the p38, JNK pathways, and NF-kappaB in CTL cybrids and offered protection against the neurotoxic effects of Abeta. Expression of SAD mitochondrial genes in cybrids activates stress-related signaling pathways and reduces viability. This SAD phenotype is produced by endogenously generated Abeta and can be replicated by exogenous Abeta acting through RAGE.
Onyango
Isaac G
IG
Center for the Study of Neurodegenerative Diseases, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Onyango@Virginia.edu
Tuttle
Jeremy B
JB
Bennett
James P
JP
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D024161:Collagen Type XI / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; C499319:COL11A2 protein, human; D024161:Collagen Type XI; D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human