title: Activation of JNK signaling mediates amyloid-ß-dependent cell death.
abstract: BACKGROUND
  Alzheimer's disease (AD) is an age related progressive neurodegenerative disorder. One of the reasons for Alzheimer's neuropathology is the generation of large aggregates of Aß42 that are toxic in nature and induce oxidative stress, aberrant signaling and many other cellular alterations that trigger neuronal cell death. However, the exact mechanisms leading to cell death are not clearly understood.
  
  
  RESULTS
  We employed a Drosophila eye model of AD to study how Aß42 causes cell death. Misexpression of higher levels of Aß42 in the differentiating photoreceptors of fly retina rapidly induced aberrant cellular phenotypes and cell death. We found that blocking caspase-dependent cell death initially blocked cell death but did not lead to a significant rescue in the adult eye. However, blocking the levels of c-Jun NH(2)-terminal kinase (JNK) signaling pathway significantly rescued the neurodegeneration phenotype of Aß42 misexpression both in eye imaginal disc as well as the adult eye. Misexpression of Aß42 induced transcriptional upregulation of puckered (puc), a downstream target and functional read out of JNK signaling. Moreover, a three-fold increase in phospho-Jun (activated Jun) protein levels was seen in Aß42 retina as compared to the wild-type retina. When we blocked both caspases and JNK signaling simultaneously in the fly retina, the rescue of the neurodegenerative phenotype is comparable to that caused by blocking JNK signaling pathway alone.
  
  
  CONCLUSIONS
  Our data suggests that (i) accumulation of Aß42 plaques induces JNK signaling in neurons and (ii) induction of JNK contributes to Aß42 mediated cell death. Therefore, inappropriate JNK activation may indeed be relevant to the AD neuropathology, thus making JNK a key target for AD therapies.
authors.affiliation: Department of Biology, University of Dayton, Dayton, Ohio, United States of America.
authors.forename: Meghana
authors.initials: M
authors.lastname: Tare
authors.forename: Rohan M
authors.initials: RM
authors.lastname: Modi
authors.forename: Jaison J
authors.initials: JJ
authors.lastname: Nainaparampil
authors.forename: Oorvashi Roy
authors.initials: OR
authors.lastname: Puli
authors.forename: Shimpi
authors.initials: S
authors.lastname: Bedi
authors.forename: Pedro
authors.initials: P
authors.lastname: Fernandez-Funez
authors.forename: Madhuri
authors.initials: M
authors.lastname: Kango-Singh
authors.forename: Amit
authors.initials: A
authors.lastname: Singh
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D002470:Cell Survival; D015536:Down-Regulation; D004331:Drosophila melanogaster / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D060227:Imaginal Discs / Q000254:growth & development / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010641:Phenotype; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D012160:Retina / Q000254:growth & development / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D048031:JNK Mitogen-Activated Protein Kinases