A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP

Proceedings of the National Academy of Sciences of the United States of America
M A LeissringFrank M Laferla

Abstract

Presenilins mediate an unusual intramembranous proteolytic activity known as gamma-secretase, two substrates of which are the Notch receptor (Notch) and the beta-amyloid precursor protein (APP). Gamma-secretase-mediated cleavage of APP, like that of Notch, yields an intracellular fragment [APP intracellular domain (AICD)] that forms a transcriptively active complex. We now demonstrate a functional role for AICD in regulating phosphoinositide-mediated calcium signaling. Genetic ablation of the presenilins or pharmacological inhibition of gamma-secretase activity (and thereby AICD production) attenuated calcium signaling in a dose-dependent and reversible manner through a mechanism involving the modulation of endoplasmic reticulum calcium stores. Cells lacking APP (and hence AICD) exhibited similar calcium signaling deficits, and-notably-these disturbances could be reversed by transfection with APP constructs containing an intact AICD, but not by constructs lacking this domain. Our findings indicate that the AICD regulates phosphoinositide-mediated calcium signaling through a gamma-secretase-dependent signaling pathway, suggesting that the intramembranous proteolysis of APP may play a signaling role analogous to that of Notch.

References

Jun 24, 1998·Genes & Development·I Greenwald
Apr 30, 1999·Science·S Artavanis-TsakonasR J Lake
Oct 12, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·C McLendonT E Golde
Jan 3, 2001·The Journal of Biological Chemistry·M S Wolfe, C Haass
Jul 10, 2001·Neurobiology of Disease·M A LeissringI Parker

❮ Previous
Next ❯

Citations

Oct 23, 2002·Journal of Neuroscience Research·Martin Citron
Jun 20, 2012·Archivum Immunologiae Et Therapiae Experimentalis·Megan M Varnum, Tsuneya Ikezu
Oct 2, 2009·Pflügers Archiv : European journal of physiology·Michael J Berridge
May 10, 2005·European Journal of Pharmacology·Daniel ParisMichael Mullan
Jun 1, 2005·Trends in Neurosciences·Rui M CostaAlcino J Silva
May 24, 2003·Biochemical and Biophysical Research Communications·Siân C PiperM Paul Murphy
Aug 30, 2002·Current Opinion in Genetics & Development·Sinisa Urban, Matthew Freeman
Feb 1, 2003·Trends in Cell Biology·Andreas Weihofen, Bruno Martoglio
Mar 28, 2003·Nature·Mark P Mattson
Jul 31, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Niki C CartyDave Morgan
Aug 6, 2004·Nature·Mark P Mattson
Jul 24, 2004·Nature Medicine·Edward H Koo, Raphael Kopan
Jan 5, 2005·Nature Reviews. Genetics·Ethan Bier
Nov 5, 2002·Nature Reviews. Neuroscience·Frank M LaFerla
Aug 7, 2013·Proceedings of the National Academy of Sciences of the United States of America·Bei WuJie Shen
Sep 8, 2007·Antioxidants & Redox Signaling·Jose ViñaMaria-Dolores Alonso
Nov 10, 2006·Molecular Biology of the Cell·Thorsten MüllerRupert Egensperger
Feb 23, 2012·Cold Spring Harbor Perspectives in Medicine·Ulrike C Müller, Hui Zheng
Mar 25, 2010·Science Signaling·Mark P Mattson
Apr 22, 2003·Annual Review of Neuroscience·Nancy M Bonini, Mark E Fortini
Mar 4, 2011·American Journal of Physiology. Cell Physiology·Cristina I LindeVera A Golovina
Oct 19, 2006·Neuro-degenerative Diseases·Brigitte Anliker, Ulrike Müller
Aug 26, 2006·Molecular Neurodegeneration·Hui Zheng, Edward H Koo
May 8, 2009·Molecular Neurodegeneration·Philippe MarambaudValérie Vingtdeux
Oct 24, 2009·Molecular Neurodegeneration·Shuji MatsudaLuciano D'Adamio
Apr 30, 2011·Molecular Neurodegeneration·Hui Zheng, Edward H Koo
Nov 26, 2010·PloS One·Alessia P M BarbagalloLuciano D'Adamio
May 17, 2011·Reviews in the Neurosciences·Karim BordjiAlain Buisson
Aug 24, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Bénédicte OulèsMounia Chami
Aug 30, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Shuji MatsudaLuciano D'Adamio
Jan 2, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Daniela PuzzoOttavio Arancio
Dec 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Natalie LandmanTae-Wan Kim
May 2, 2007·Proceedings of the National Academy of Sciences of the United States of America·Huifang MaKaren H Ashe
Aug 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Richard G JennerPaul Kellam

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alzheimer's Disease: APP

Amyloid precursor protein (APP) proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques in the brain. Here is the latest research on APP and Alzheimer's disease.

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.