A short cytoplasmic domain of the amyloid precursor protein induces apoptosis in vitro and in vivo

Molecular and Cellular Neurosciences
E BertrandBernadette Allinquant

Abstract

The amyloid precursor protein presents several cleavage sites leading to the release of its entire C-terminal domain into the cytoplasm. During apoptosis, this C-terminal domain can be cleaved at amino acid 664 by caspases 3, 6, and 8 and can thus generate two peptides N- and C-terminal to amino acid 664 (C31). Recently, it was shown that the C31 induces apoptosis after transfection into N2A and 293 T cell lines. We have analyzed here, by internalization into neurons, the physiological consequences of the entire C-terminal domain (APP-Cter) and of its membrane proximal sequence corresponding to the N-terminal peptide unmasked after caspase cleavage. We find that whereas micromolar concentrations of APP-Cter are harmless, the peptide extending from the membrane (amino acid 649) to the caspase cleavage site (amino acid 664) in the same range of concentrations induces DNA fragmentation, cleavage of actin at a caspase-sensitive site, and activates caspase 3. A mutated version of this sequence (tyrosine 653 replaced by an aspartate) abolishes the effect in vitro and in vivo. Taken together, this report suggests the existence of a new mechanism contributing to Alzheimer's Disease-associated cell death.

References

Feb 24, 1995·The Journal of Biological Chemistry·A LaiI S Trowbridge
Aug 8, 1998·Trends in Cell Biology·D DerossiA Prochiantz
Dec 9, 1998·Proceedings of the National Academy of Sciences of the United States of America·P ZhengS W Pimplikar
Jun 23, 1999·Proceedings of the National Academy of Sciences of the United States of America·X XuL Mucke
Aug 7, 1999·The Journal of Biological Chemistry·A LeBlancJ Hammond
Aug 6, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·H S KimY H Suh
Sep 6, 2000·The European Journal of Neuroscience·S J BoltonF S Walsh

❮ Previous
Next ❯

Citations

May 25, 2013·EMBO Molecular Medicine·Dale E Bredesen, Varghese John
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
Aug 26, 2006·Molecular Neurodegeneration·Hui Zheng, Edward H Koo
Apr 30, 2011·Molecular Neurodegeneration·Hui Zheng, Edward H Koo
Mar 8, 2013·PloS One·Tina FiorelliJaya Padmanabhan
Aug 19, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Carmela MatroneLuciano D'Adamio
Jan 8, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Julie A HarrisLennart Mucke
Aug 3, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Roger LefortMichael Shelanski
May 7, 2003·Proceedings of the National Academy of Sciences of the United States of America·Bonnie C MillerDwain L Thiele
Jul 2, 2014·BMC Neuroscience·Stéphanie ChasseigneauxBernadette Allinquant
Aug 15, 2009·Biochemical and Biophysical Research Communications·Sun Ah ParkEdward H Koo
Feb 3, 2007·Progress in Neurobiology·Slavica KranticRémi Quirion
Mar 24, 2009·Journal of Cellular Physiology·Mary C VázquezAlejandra R Alvarez
Oct 11, 2003·Journal of Neurochemistry·Daniel C LuEdward H Koo
Nov 15, 2006·The European Journal of Neuroscience·X MecklerA Hémar
Oct 28, 2005·The EMBO Journal·Constanze ReinhardBart De Strooper
Nov 30, 2011·Journal of Neurochemistry·Han ZhangHuaxi Xu
Sep 18, 2015·Neurochemical Research·Natalia N NalivaevaAnthony J Turner
Aug 21, 2012·Biochimica Et Biophysica Acta·Thorsten MüllerKatrin Marcus
Nov 23, 2006·Biochimica Et Biophysica Acta·Rachael L Neve, Donna L McPhie
Nov 25, 2018·British Journal of Pharmacology·M Isabel G Lopez SanchezIan A Trounce
Sep 16, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·A MadeiraB Allinquant
Apr 2, 2004·Journal of Neuropathology and Experimental Neurology·Hiroshi TakumaHiroshi Mori
Jun 5, 2015·Oncotarget·Alexei Kurakin, Dale E Bredesen
May 30, 2019·Cellular and Molecular Life Sciences : CMLS·Aysegul Dilsizoglu SenolBernadette Allinquant
Nov 22, 2019·Frontiers in Cellular Neuroscience·Ana María Espinosa-OlivaMiguel Angel Burguillos
Oct 15, 2019·Frontiers in Aging Neuroscience·Laura García-GonzálezSantiago Rivera
Aug 16, 2017·Neurochemistry International·Alex E RoherThomas G Beach

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptotic Caspases

Apoptotic caspases belong to the protease enzyme family and are known to play an essential role in inflammation and programmed cell death. Here is the latest research.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.

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.