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.
References
Jun 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·K S KosikD J Selkoe
Jul 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·I Grundke-IqbalL I Binder
Nov 25, 1988·Journal of Immunological Methods·T Decker, M L Lohmann-Matthes
Dec 20, 1996·The Journal of Biological Chemistry·G CarmelJ Kuret
Jan 1, 1997·Journal of Neurochemistry·G V JohnsonD Galasko
Jan 17, 1997·The Journal of Biological Chemistry·R P GuttmannG V Johnson
Jan 1, 1997·Journal of Cellular Biochemistry·A Rosen, L Casciola-Rosen
Aug 15, 1997·The Biochemical Journal·G M Cohen
Nov 18, 1998·Journal of Neuroscience Research·E R BongarzoneA T Campagnoni
Feb 16, 2000·Neurobiology of Aging·E GroberR B Lipton
Mar 14, 2000·The Journal of Biological Chemistry·G N BijurR S Jope
Jul 19, 2000·Journal of Neurochemistry·L FasuloA Cattaneo
Aug 24, 2000·Journal of Neuroscience Research·P K KrishnamurthyG V Johnson
Feb 13, 2001·Neurobiology of Disease·C W ChungY K Jung
Jul 31, 2003·Proceedings of the National Academy of Sciences of the United States of America·T Chris GamblinVincent L Cryns
Dec 9, 2003·The Journal of Biological Chemistry·Pavan K Krishnamurthy, Gail V W Johnson
Feb 3, 2004·Journal of Cellular and Molecular Medicine·A Verkhratsky, E C Toescu
Feb 14, 2004·Human Molecular Genetics·Qingmin RuanGail V W Johnson
Mar 30, 2004·Journal of Neuroscience Research·Shirley B SheltonGail V W Johnson
Jul 3, 2004·The Journal of Clinical Investigation·Robert A RissmanCarl W Cotman
Sep 24, 2004·Science's STKE : Signal Transduction Knowledge Environment·Eric C C Cheung, Ruth S Slack
Dec 9, 2004·Journal of Cell Science·Anna J KimGeoff H Werstuck
Mar 8, 2005·Journal of Alzheimer's Disease : JAD·Luisa FasuloAntonino Cattaneo
Jun 24, 2005·Acta Neuropathologica·J J M HoozemansW Scheper
Aug 10, 2005·Cell Calcium·Wulf Paschen, Thorsten Mengesdorf
May 23, 2006·The Journal of Biological Chemistry·Young Hae ChongAndrea J Tenner
Feb 10, 2007·The FEBS Journal·Hiderou Yoshida
Jan 25, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Tara L Spires-JonesBradley T Hyman
Citations
Jan 27, 2010·Molecular Neurobiology·Bo SuXiongwei Zhu
May 15, 2010·The Journal of Biological Chemistry·Philip J Dolan, Gail V W Johnson
Apr 25, 2009·The Journal of Biological Chemistry·Rodrigo A QuintanillaGail 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
May 15, 2015·Scientific Reports·Maxime DerisbourgMalika Hamdane
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
May 26, 2016·Neurochemical Research·John C MeansPeter Koulen
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
Jan 26, 2021·Frontiers in Neurology·Carolina AlquezarAimee W Kao
Mar 3, 2021·Cell Death & Disease·Anastasia NoëlAndréa C LeBlanc
May 26, 2020·Current Neuropharmacology·Rodrigo A Quntanilla, Carola Tapia-Monsalves