Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo

Nature
Dominic M WalshDennis J Selkoe

Abstract

Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Abeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Abeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Abeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Abeta oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium ...Continue Reading

References

May 1, 1995·Neurobiology of Aging·D W DicksonP Davies
Apr 21, 1995·The Journal of Biological Chemistry·M B PodlisnyD J Selkoe
Dec 6, 1994·Proceedings of the National Academy of Sciences of the United States of America·A Lorenzo, B A Yankner
May 30, 1998·Proceedings of the National Academy of Sciences of the United States of America·M P LambertW L Klein
Nov 26, 1998·The Journal of Biological Chemistry·W Q QiuD J Selkoe
Mar 17, 1999·Proceedings of the National Academy of Sciences of the United States of America·A Y HsiaL Mucke
Mar 31, 1999·Proceedings of the National Academy of Sciences of the United States of America·F ChitiC M Dobson
Aug 28, 1999·The Journal of Biological Chemistry·D M WalshD B Teplow
Feb 19, 2000·Current Opinion in Structural Biology·J C Rochet, P T Lansbury
Jun 2, 2000·Protein Expression and Purification·V Chesneau, M R Rosner
Aug 2, 2000·Proceedings of the National Academy of Sciences of the United States of America·W XiaD J Selkoe
Mar 29, 2001·Physiological Reviews·D J Selkoe

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Citations

Feb 11, 2009·Archives of Neurology·Jorge J Palop, Lennart Mucke
Nov 11, 2009·Archives of Neurology·Haakon B Nygaard, Stephen M Strittmatter
Sep 5, 2002·Journal of Neuroscience Research·Marina D KirkitadzeDavid B Teplow
Oct 23, 2002·Journal of Neuroscience Research·Bruce Teter, J Wesson Ashford
May 28, 2003·Mass Spectrometry Reviews·Lars Konermann, Douglas A Simmons
Nov 27, 2002·Journal of Peptide Science : an Official Publication of the European Peptide Society·Francesc RabanalErnest Giralt
May 24, 2007·Molecular Neurobiology·Michael T Maloney, James R Bamburg
Jan 11, 2005·Neurotoxicity Research·Gillian C Gregory, Glenda M Halliday
Jan 19, 2008·Neurotoxicity Research·Rommy von Bernhardi
Jun 20, 2012·Archivum Immunologiae Et Therapiae Experimentalis·Megan M Varnum, Tsuneya Ikezu
May 27, 2008·Cellular and Molecular Life Sciences : CMLS·B Waldau, A K Shetty
Jun 28, 2011·Cellular and Molecular Life Sciences : CMLS·Jürgen GötzXin Liu
Aug 19, 2008·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Anne EckertJürgen Götz
Dec 5, 2009·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Erik C Gunther, Stephen M Strittmatter
Mar 11, 2010·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Mariagioia ZampagniCristina Cecchi
Mar 27, 2013·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Gregor P Lotz, Justin Legleiter
May 27, 2010·Analytical and Bioanalytical Chemistry·Henning WibergJohan Roeraade
Feb 11, 2005·The Journal of Membrane Biology·B L KaganR Azimova
May 12, 2007·European Biophysics Journal : EBJ·Rita CarrottaPier Luigi San Biagio
Dec 8, 2007·European Biophysics Journal : EBJ·Ryan NaylorKevin J Barnham
Apr 4, 2008·European Biophysics Journal : EBJ·Zuzana GazovaMarian Antalik
May 24, 2006·Acta Neuropathologica·Rudy J CastellaniMark A Smith
Nov 27, 2007·Acta Neuropathologica·Charles DuyckaertsBenoît Delatour
Mar 24, 2009·Acta Neuropathologica·Claire ShepherdGlenda Margaret Halliday
Apr 22, 2009·Acta Neuropathologica·Charles DuyckaertsMarie-Claude Potier
Apr 25, 2009·Acta Neuropathologica·Thomas Arendt
Apr 1, 2010·Acta Neuropathologica·Gunnar K GourasEstibaliz Capetillo-Zarate
Jul 16, 2010·Acta Neuropathologica·Delphine BocheJames A R Nicoll
Jan 29, 2013·Acta Neuropathologica·Andrew D WattKevin J Barnham
Oct 2, 2009·Pflügers Archiv : European journal of physiology·Michael J Berridge
Sep 1, 2011·Cell and Tissue Research·Filippo CaraciAgata Copani
Feb 14, 2009·Journal of Neural Transmission·Philipp GörtzChristian Lange-Asschenfeldt
Jul 16, 2010·Journal of Neural Transmission·Michael T HenekaMarkus Peter Kummer
Nov 17, 2011·Journal of Neural Transmission·Nady BraidyGilles J Guillemin
Dec 4, 2004·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Xudong HuangAshley I Bush
Feb 24, 2010·Journal of Artificial Organs : the Official Journal of the Japanese Society for Artificial Organs·Kazunori KawaguchiSatoshi Sugiyama
Dec 6, 2012·Journal of Artificial Organs : the Official Journal of the Japanese Society for Artificial Organs·Kazunori KawaguchiNobuya Kitaguchi

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