PMID- 24860020 OWN - NLM STAT- MEDLINE DCOM- 20160510 LR - 20150815 IS - 1460-2199 (Electronic) IS - 1047-3211 (Linking) VI - 25 IP - 9 DP - 2015 Sep TI - Dysregulation of TrkB Receptors and BDNF Function by Amyloid-beta Peptide is Mediated by Calpain. PG - 3107-21 LID - 10.1093/cercor/bhu105 [doi] AB - Brain-derived neurotrophic factor (BDNF) and its high-affinity full-length (FL) receptor, TrkB-FL, play a central role in the nervous system by providing trophic support to neurons and regulating synaptic plasticity and memory. TrkB and BDNF signaling are impaired in Alzheimer's disease (AD), a neurodegenerative disease involving accumulation of amyloid-beta (Abeta) peptide. We recently showed that Abeta leads to a decrease of TrkB-FL receptor and to an increase of truncated TrkB receptors by an unknown mechanism. In the present study, we found that (1) Abeta selectively increases mRNA levels for the truncated TrkB isoforms without affecting TrkB-FL mRNA levels, (2) Abeta induces a calpain-mediated cleavage on TrkB-FL receptors, downstream of Shc-binding site, originating a new truncated TrkB receptor (TrkB-T') and an intracellular fragment (TrkB-ICD), which is also detected in postmortem human brain samples, (3) Abeta impairs BDNF function in a calpain-dependent way, as assessed by the inability of BDNF to modulate neurotransmitter (GABA and glutamate) release from hippocampal nerve terminals, and long-term potentiation in hippocampal slices. It is concluded that Abeta-induced calpain activation leads to TrkB cleavage and impairment of BDNF neuromodulatory actions. CI - (c) The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. FAU - Jeronimo-Santos, Andre AU - Jeronimo-Santos A AD - Instituto de Farmacologia e Neurociencias, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociencias, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal. FAU - Vaz, Sandra Henriques AU - Vaz SH AD - Instituto de Farmacologia e Neurociencias, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociencias, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal. FAU - Parreira, Sara AU - Parreira S AD - Instituto de Farmacologia e Neurociencias, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociencias, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal. FAU - Rapaz-Lerias, Sofia AU - Rapaz-Lerias S AD - Instituto de Farmacologia e Neurociencias, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociencias, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal. FAU - Caetano, Antonio P AU - Caetano AP AD - Instituto de Farmacologia e Neurociencias, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociencias, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal. FAU - Buee-Scherrer, Valerie AU - Buee-Scherrer V AD - Universite Lille-Nord de France, UDSL, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, Lille, France CHRU-Lille, F-59000, Lille, France. FAU - Castren, Eero AU - Castren E AD - Neuroscience Center, University of Helsinki, PO Box 56, 00014 Helsinki, Finland. FAU - Valente, Claudia A AU - Valente CA AD - Instituto de Farmacologia e Neurociencias, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociencias, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal. FAU - Blum, David AU - Blum D AD - Universite Lille-Nord de France, UDSL, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, Lille, France CHRU-Lille, F-59000, Lille, France. FAU - Sebastiao, Ana Maria AU - Sebastiao AM AD - Instituto de Farmacologia e Neurociencias, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociencias, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal. FAU - Diogenes, Maria Jose AU - Diogenes MJ AD - Instituto de Farmacologia e Neurociencias, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociencias, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140523 PL - United States TA - Cereb Cortex JT - Cerebral cortex (New York, N.Y. : 1991) JID - 9110718 RN - 0 (Amyloid beta-Peptides) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Enzyme Inhibitors) RN - 3KX376GY7L (Glutamic Acid) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 3.4.22.- (Calpain) SB - IM MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Brain/cytology MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Calpain/*pharmacology MH - Embryo, Mammalian MH - Enzyme Inhibitors/pharmacology MH - Female MH - Frontal Lobe/*drug effects MH - Gene Expression Regulation/drug effects MH - Glutamic Acid/metabolism MH - Humans MH - Long-Term Potentiation/drug effects/physiology MH - Male MH - Neurons/*drug effects MH - Pregnancy MH - Rats MH - Rats, Sprague-Dawley MH - Rats, Wistar MH - Receptor, trkB/genetics/*metabolism MH - Synaptosomes/drug effects/metabolism MH - gamma-Aminobutyric Acid/metabolism OTO - NOTNLM OT - Alzheimer's disease OT - LTP OT - MDL28170 OT - neurodegeneration OT - neurotrophins EDAT- 2014/05/27 06:00 MHDA- 2016/05/11 06:00 CRDT- 2014/05/27 06:00 PHST- 2014/05/27 06:00 [entrez] PHST- 2014/05/27 06:00 [pubmed] PHST- 2016/05/11 06:00 [medline] AID - bhu105 [pii] AID - 10.1093/cercor/bhu105 [doi] PST - ppublish SO - Cereb Cortex. 2015 Sep;25(9):3107-21. doi: 10.1093/cercor/bhu105. Epub 2014 May 23.