The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis.

Authors:
Dr Caroline Bonner, PhD
Dr Caroline Bonner, PhD
Institue Pasteur, Lille, France, Affiliated with Inserm UMR 1190 Translational Research for Diabetes
Senior Research Scientist: Novel therapies for type 2 diabetes
Human Islet Biology / Physiology and Disease
Lille, Lille | France

Neurobiol Aging 2012 Sep 30;33(9):2200-9. Epub 2011 Jul 30.

Experimental Neurosurgery, Center for Neurology and Neurosurgery, Goethe University Hospital, Frankfurt, Germany.

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.

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http://dx.doi.org/10.1016/j.neurobiolaging.2011.06.012DOI Listing
September 2012
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