Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease.
Neuronal death is a pathological hallmark of Alzheimer's disease. We have shown previously that phosphorylated double-stranded RNA-dependent protein kinase is present in degenerating hippocampal neurons and in senile plaques of Alzheimer's disease brains and that genetically down-regulating double-stranded RNA-dependent protein kinase activity protects against in vitro beta-amyloid peptide neurotoxicity. In this report, we showed that two double-stranded RNA-dependent protein kinase blockers attenuate, in human neuroblastoma cells, beta-amyloid peptide toxicity evaluated by caspase 3 assessment. In addition, we have used the newly engineered APP(SL)/presenilin 1 knock-in transgenic mice, which display a severe neuronal loss in hippocampal regions, to analyze the activation of double-stranded RNA-dependent protein kinase. Western blots revealed the increased levels of activated double-stranded RNA-dependent protein kinase and the inhibition of eukaryotic initiation factor 2 alpha activity in the brains of these double transgenic mice. Phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum-resident kinase was also increased in the brains of these mice. The levels of activated double-stranded RNA-dependent protein kinase were also increased in the brains of patients with Alzheimer's disease. At 3, 6 and 12 months, hippocampal neurons display double stranded RNA-dependent protein kinase labelings in both the nucleus and the cytoplasm. Confocal microscopy showed that almost constantly activated double-stranded RNA-dependent protein kinase co-localized with DNA strand breaks in apoptotic nuclei of CA1 hippocampal neurons. Taken together these results demonstrate that double-stranded RNA-dependent protein kinase is associated with neurodegeneration in APP(SL)/presenilin 1 knock-in mice and could represent a new therapeutic target for neuroprotection.
Research Group on Brain Aging (EA 3808), University of Poitiers, France. guylene.page@univ-poitiers.fr
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Rioux Bilan
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Ingrand
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Lafay-Chebassier
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Perault Pochat
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Bouras
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D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D010450:Endopeptidases / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010446:Peptide Fragments / Q000633:toxicity; D053764:Presenilin-1; D019892:eIF-2 Kinase / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007211:Indoles; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C007293:DAPI; D019892:eIF-2 Kinase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse