title: The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis.
abstract: Here we employed human SHEP neuroblastoma cells either stably or inducibly expressing the amyloid precursor protein (APP) intracellular domain (AICD) to investigate its ability to modulate stress-induced cell death. Analysis of effector caspase activation revealed that AICD overexpression was specifically associated with an increased sensitivity to apoptosis induced by the 2 endoplasmic reticulum (ER) stressors thapsigargin and tunicamycin, but not by staurosporine (STS). Basal and ER stress-induced expression of Bip/Grp78 and C/EBP-homologous protein/GADD153 were not altered by AICD implying that AICD potentiated cell death downstream or independent of the conserved unfolded protein response (UPR). Interestingly, quantitative polymerase chain reaction analysis and reporter gene assays revealed that AICD significantly downregulated messenger RNA levels of the Alzheimer's disease susceptibility gene ApoJ/clusterin, indicating transcriptional repression. Knockdown of ApoJ/clusterin mimicked the effect of AICD on ER stress-induced apoptosis, but had no discernible effect on staurosporine-induced cell death. Our data suggest that altered levels of AICD may abolish the prosurvival function of ApoJ/clusterin and increase the susceptibility of neurons to ER stress-mediated cell death, a pathway that may contribute to the pathogenesis of Alzheimer's disease.
authors.affiliation: Experimental Neurosurgery, Center for Neurology and Neurosurgery, Goethe University Hospital, Frankfurt, Germany.
authors.forename: Donat
authors.initials: D
authors.lastname: Kögel
authors.forename: Caoimhín G
authors.initials: CG
authors.lastname: Concannon
authors.forename: Thorsten
authors.initials: T
authors.lastname: Müller
authors.forename: Hildegard
authors.initials: H
authors.lastname: König
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonner
authors.forename: Simone
authors.initials: S
authors.lastname: Poeschel
authors.forename: Steffi
authors.initials: S
authors.lastname: Chang
authors.forename: Rupert
authors.initials: R
authors.lastname: Egensperger
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D051152:Clusterin / Q000235:genetics / Q000378:metabolism; D003564:Cytidine Deaminase / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D051152:Clusterin; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D014415:Tunicamycin; D049452:Green Fluorescent Proteins; D019284:Thapsigargin; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase