Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Claudia G AlmeidaGunnar K Gouras

Abstract

Increasing evidence links intraneuronal beta-amyloid (Abeta42) accumulation with the pathogenesis of Alzheimer's disease (AD). In Abeta precursor protein (APP) mutant transgenic mice and in human AD brain, progressive intraneuronal accumulation of Abeta42 occurs especially in multivesicular bodies (MVBs). We hypothesized that this impairs the MVB sorting pathway. We used the trafficking of the epidermal growth factor receptor (EGFR) and TrkB receptor to investigate the MVB sorting pathway in cultured neurons. We report that, during EGF stimulation, APP mutant neurons demonstrated impaired inactivation, degradation, and ubiquitination of EGFR. EGFR degradation is dependent on translocation from MVB outer to inner membranes, which is regulated by the ubiquitin-proteasome system (UPS). We provide evidence that Abeta accumulation in APP mutant neurons inhibits the activities of the proteasome and deubiquitinating enzymes. These data suggest a mechanism whereby Abeta accumulation in neurons impairs the MVB sorting pathway via the UPS in AD.

Citations

Jul 16, 2008·Archives of Neurology·Joshua R SteinermanYaakov Stern
Mar 11, 2010·Acta Neuropathologica·Ditte Z ChristensenOliver Wirths
Apr 1, 2010·Acta Neuropathologica·Gunnar K GourasEstibaliz Capetillo-Zarate
Mar 1, 2012·Molecular Neurobiology·Tobias MoraweChristian Behl
Jul 21, 2012·Molecular Neurobiology·Ricardo J S VianaCecília M P Rodrigues
Jun 21, 2011·Expert Reviews in Molecular Medicine·Tae Ho LeeKun Ping Lu
Jul 29, 2011·Journal of the American Chemical Society·Gabriele S Kaminski SchierleClemens F Kaminski
Nov 8, 2006·Nature Medicine·Michael T Lin, M Flint Beal
Jun 7, 2007·Nature Reviews. Neuroscience·Frank M LaFerlaSalvatore Oddo
Mar 24, 2009·Proceedings of the National Academy of Sciences of the United States of America·Herman MorenoRodolfo R Llinás
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Ralf P FriedrichMarcus Fändrich
Jul 21, 2010·Proceedings of the National Academy of Sciences of the United States of America·Valentin LulevichGang-yu Liu
Sep 29, 2012·Proceedings of the National Academy of Sciences of the United States of America·Lei WangYi Zhong
May 1, 2010·The Journal of Biological Chemistry·Rui-Qin LiuSen-Fang Sui
Jan 9, 2009·The Journal of Biological Chemistry·Linda HasadsriJulia M George
Dec 17, 2008·The Journal of Biological Chemistry·Siddhartha MitraSteven Finkbeiner
Feb 11, 2009·Molecular & Cellular Proteomics : MCP·Flip H JansenGuido Jenster
Apr 23, 2013·Brain : a Journal of Neurology·Marie OrreElly M Hol
Jul 5, 2012·Cold Spring Harbor Perspectives in Medicine·Lennart Mucke, Dennis J Selkoe
Nov 11, 2010·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Reisuke H TakahashiHidehiro Takahashi
May 18, 2007·Annual Review of Cell and Developmental Biology·Robert C Piper, David J Katzmann
Dec 6, 2007·BMC Biochemistry·Sudarshan C Upadhya, Ashok N Hegde
Aug 14, 2012·Disease Models & Mechanisms·Fabien D'AngeloChristelle Marchal
May 16, 2008·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Naoki HattoriChiyoko Inagaki
Aug 12, 2010·Channels·Pradeep KurupPaul J Lombroso
Aug 7, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Davide TampelliniGunnar K Gouras
Oct 28, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Davide TampelliniGunnar K Gouras
Dec 7, 2013·International Journal of Cell Biology·Gunnar K Gouras
Feb 26, 2011·International Journal of Alzheimer's Disease·Amany Mohamed, Elena Posse de Chaves
Aug 26, 2014·Cellular and Molecular Life Sciences : CMLS·Tae-In KamYong-Keun Jung
May 26, 2012·Canadian Journal of Physiology and Pharmacology·Elena Posse de Chaves
Aug 3, 2010·Biochimica Et Biophysica Acta·Ashok N Hegde, Sudarshan C Upadhya
Dec 6, 2008·Seminars in Cell & Developmental Biology·Ragna Sannerud, Wim Annaert
Sep 6, 2008·Neurobiology of Aging·Reisuke H TakahashiGunnar K Gouras
May 2, 2008·Progress in Neurobiology·Paula van TijnDavid F Fischer
Mar 25, 2008·Molecular and Cellular Endocrinology·E Burgos-RamosE Arilla-Ferreiro

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