Immortalized cortical neurons expressing caspase-cleaved tau are sensitized to endoplasmic reticulum stress induced cell death.

Brain Research
Tori A Matthews-RobersonGail V W Johnson

Abstract

It has been previously reported that an Asp421 cleaved form of tau is toxic when expressed in cells. The purpose of this study was to understand if, and in what manner, the presence of Asp421 cleaved tau in neurons, which is generated by caspase cleavage, might facilitate neuronal death in Alzheimer's disease (AD). For these studies we used immortalized cortical neurons that inducibly express either a full-length tau isoform (T4) or an isoform that has been pseudo-truncated at Asp421 (T4C3), to mimic caspase-3 cleavage. Neurons expressing either T4 or T4C3 were treated with thapsigargin, a drug, which has been shown to induce endoplasmic reticulum (ER) stress. Following long-term treatment with thapsigargin, cells expressing T4C3 presented with a marked increase in cell toxicity, underscored by differential activation of caspase-3 in comparison with cells expressing T4. Furthermore, we found that an inhibitor of the ERK1/2 signaling pathway, which is upregulated to different extents in each cell type, significantly reduced toxicity in both T4 and T4C3 cells. Our results suggest that the presence of Asp421 cleaved tau may sensitize neurons to ER stressors and possibly potentiate cell death processes during AD progression.

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Citations

May 15, 2010·The Journal of Biological Chemistry·Philip J Dolan, Gail V W Johnson
Mar 17, 2009·Molecular Neurodegeneration·Tania F Gendron, Leonard Petrucelli
Jul 29, 2010·PLoS Genetics·Vikram KhuranaMel B Feany
Aug 20, 2014·Neurobiology of Disease·Rodrigo A QuintanillaGail V W Johnson
Nov 15, 2013·Journal of Neuropathology and Experimental Neurology·Jose J Jarero-BasultoFrancisco Garcia-Sierra
Feb 26, 2011·Journal of Cellular and Molecular Medicine·Susanne M PritchardGail V W Johnson
Jun 13, 2012·International Journal of Alzheimer's Disease·Michala KolarovaDaniela Ripova
Apr 1, 2011·Neurobiology of Aging·Rodrigo A QuintanillaGail V W Johnson
Mar 24, 2016·Journal of Alzheimer's Disease : JAD·Francisco M Torres-CruzFrancisco Garcia-Sierra
Jan 14, 2017·Molecular Neurobiology·María José PérezRodrigo A Quintanilla
Dec 7, 2018·Journal of Alzheimer's Disease : JAD·Hasan A M M AlmansoubDan Liu
Apr 10, 2018·Journal of Alzheimer's Disease : JAD·James P QuinnNigel M Hooper
May 26, 2020·Current Neuropharmacology·Rodrigo A Quntanilla, Carola Tapia-Monsalves

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