title: Dysregulation of TrkB Receptors and BDNF Function by Amyloid-β Peptide is Mediated by Calpain.
abstract: 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-β (Aβ) peptide. We recently showed that Aβ 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) Aβ selectively increases mRNA levels for the truncated TrkB isoforms without affecting TrkB-FL mRNA levels, (2) Aβ 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) Aβ 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 Aβ-induced calpain activation leads to TrkB cleavage and impairment of BDNF neuromodulatory actions.
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
authors.forename: André
authors.initials: A
authors.lastname: Jerónimo-Santos
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
authors.forename: Sandra Henriques
authors.initials: SH
authors.lastname: Vaz
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Parreira
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Rapaz-Lérias
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
authors.forename: António P
authors.initials: AP
authors.lastname: Caetano
authors.affiliation: Université Lille-Nord de France, UDSL, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, Lille, France CHRU-Lille, F-59000, Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Buée-Scherrer
authors.affiliation: Neuroscience Center, University of Helsinki, PO Box 56, 00014 Helsinki, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Castrén
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Valente
authors.affiliation: Université Lille-Nord de France, UDSL, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, Lille, France CHRU-Lille, F-59000, Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Sebastião
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Diógenes
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002154:Calpain / Q000494:pharmacology*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D020813:Receptor, trkB; D002154:Calpain
keywords: Alzheimer's disease; LTP; MDL28170; neurodegeneration; neurotrophins