Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein

Nature
Bart De StrooperF Van Leuven

Abstract

Point mutations in the presenilin-1 gene (PS1) are a major cause of familial Alzheimer's disease. They result in a selective increase in the production of the amyloidogenic peptide amyloid-beta(1-42) by proteolytic processing of the amyloid precursor protein (APP). Here we investigate whether PS1 is also involved in normal APP processing in neuronal cultures derived from PS1-deficient mouse embryos. Cleavage by alpha- and beta-secretase of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by gamma-secretase of the transmembrane domain of APP was prevented, causing carboxyl-terminal fragments of APP to accumulate and a fivefold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. As in the regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheim...Continue Reading

References

Nov 1, 1996·The Journal of Biological Chemistry·P SaftigB De Strooper
Nov 12, 1996·Proceedings of the National Academy of Sciences of the United States of America·M CitronD J Selkoe
Nov 1, 1996·Neuron·X Li, I Greenwald
Nov 1, 1996·Neuron·A DoanS S Sisodia
Dec 10, 1996·Proceedings of the National Academy of Sciences of the United States of America·D LevitanI Greenwald
Apr 1, 1997·Trends in Neurosciences·J Hardy
Apr 15, 1997·Proceedings of the National Academy of Sciences of the United States of America·P J TienariK Beyreuther
May 2, 1997·The Journal of Biological Chemistry·S LehmannD A Harris
May 1, 1997·Neuron·C Haass
Jul 22, 1997·Proceedings of the National Academy of Sciences of the United States of America·W XiaD J Selkoe

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Citations

Oct 6, 2000·Journal of Neuroscience Research·M NakajimaT Shirasawa
Apr 11, 2012·EMBO Molecular Medicine·Francesc X GuixBart De Strooper
Oct 23, 2002·Journal of Neuroscience Research·Maho Morishima-Kawashima, Yasuo Ihara
Jun 29, 2001·Journal of Peptide Science : an Official Publication of the European Peptide Society·A B ClippingdaleC J Barrow
Sep 24, 1999·Molecular Neurobiology·F Checler
Jun 11, 2008·Der Nervenarzt·T GrimmerA Kurz
Nov 27, 2007·Naunyn-Schmiedeberg's Archives of Pharmacology·Taisuke Tomita
Jun 7, 2005·Experimental Brain Research·Kina HöglundKaj Blennow
Nov 29, 2011·Experimental Brain Research·Johannes ProxPaul Saftig
Mar 24, 2009·Acta Neuropathologica·Claire ShepherdGlenda Margaret Halliday
Nov 10, 2012·Acta Neuropathologica·Lara WahlsterOksana Berezovska
Oct 14, 2004·Neurogenetics·Wiep ScheperFrank Baas
Apr 11, 2012·Cellular and Molecular Neurobiology·Gavin R Owen, Elisabeth Anne Brenner
Aug 10, 2006·Glycoconjugate Journal·Shinobu KitazumeYasuhiro Hashimoto
Sep 1, 2006·Neurochemical Research·Giuseppe VerdileRalph N Martins
Jul 1, 2000·Journal of the American Aging Association·D Harman
Aug 10, 2002·Current Neurology and Neuroscience Reports·Joanna L JankowskyDavid R Borchelt
Dec 10, 2009·Molecular Neurobiology·Masaaki Matsuoka, Yuichi Hashimoto
Jul 16, 2008·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Michael S Wolfe
Apr 23, 2003·FEBS Letters·Sigfrido ScarpaRosaria A Cavallaro
Jul 7, 1999·Neuroscience and Biobehavioral Reviews·E Gahtan, J B Overmier
Sep 11, 1999·Trends in Neurosciences·W Annaert, B De Strooper
Jul 2, 2003·Cellular Signalling·Miguel Medina, Carlos G Dotti
Jul 17, 1999·Trends in Cell Biology·C Haass, E Mandelkow
Oct 27, 1998·Trends in Biochemical Sciences·J KimbleS Crittenden
Feb 20, 2009·Chemical Reviews·Michael S Wolfe
Jun 11, 1999·Clinical Genetics·M NishimuraP H St George-Hyslop
May 23, 2003·Nature·Bart De Strooper, James Woodgett
Mar 28, 2003·Nature·Nobumasa TakasugiTakeshi Iwatsubo
May 23, 2003·Nature·Christopher J PhielPeter S Klein
Jan 2, 2007·Nature Biotechnology·Parag MallickRuedi Aebersold
Dec 2, 2010·Nature Communications·Kengo UemuraOksana Berezovska

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