title: Transthyretin provides trophic support via megalin by promoting neurite outgrowth and neuroprotection in cerebral ischemia.
abstract: Transthyretin (TTR) is a protein whose function has been associated to binding and distribution of thyroid hormones in the body and brain. However, little is known regarding the downstream signaling pathways triggered by wild-type TTR in the CNS either in neuroprotection of cerebral ischemia or in physiological conditions. In this study, we investigated how TTR affects hippocampal neurons in physiologic/pathologic conditions. Recombinant TTR significantly boosted neurite outgrowth in mice hippocampal neurons, both in number and length, independently of its ligands. This TTR neuritogenic activity is mediated by the megalin receptor and is lost in megalin-deficient neurons. We also found that TTR activates the mitogen-activated protein kinase (MAPK) pathways (ERK1/2) and Akt through Src, leading to the phosphorylation of transcription factor CREB. In addition, TTR promoted a transient rise in intracellular calcium through NMDA receptors, in a Src/megalin-dependent manner. Moreover, under excitotoxic conditions, TTR stimulation rescued cell death and neurite loss in TTR KO hippocampal neurons, which are more sensitive to excitotoxic degeneration than WT neurons, in a megalin-dependent manner. CREB was also activated by TTR under excitotoxic conditions, contributing to changes in the balance between Bcl2 protein family members, toward anti-apoptotic proteins (Bcl2/BclXL versus Bax). Finally, we clarify that TTR KO mice subjected to pMCAO have larger infarcts than WT mice, because of TTR and megalin neuronal downregulation. Our results indicate that TTR might be regarded as a neurotrophic factor, because it stimulates neurite outgrowth under physiological conditions, and promotes neuroprotection in ischemic conditions.
authors: Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Porto, Portugal.|Molecular Neurobiology Unit, IBMC- Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal.
authors: J R
authors: JR
authors: Gomes
authors: Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Porto, Portugal.|Molecular Neurobiology Unit, IBMC- Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal.
authors: R S
authors: RS
authors: Nogueira
authors: Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Porto, Portugal.|Molecular Neurobiology Unit, IBMC- Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal.
authors: M
authors: M
authors: Vieira
authors: Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Porto, Portugal.|Glial Cell Biology Unit, IBMC- Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal.
authors: S D
authors: SD
authors: Santos
authors: Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Porto, Portugal.|Glial Cell Biology Unit, IBMC- Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal.
authors: J P
authors: JP
authors: Ferraz-Nogueira
authors: Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Porto, Portugal.|Glial Cell Biology Unit, IBMC- Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal.
authors: J B
authors: JB
authors: Relvas
authors: Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Porto, Portugal.|Molecular Neurobiology Unit, IBMC- Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal.|ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313 Porto, Portugal.
authors: M J
authors: MJ
authors: Saraiva
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071446:Neuronal Outgrowth / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity; D011228:Prealbumin / Q000378:metabolism* / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D009498:Neurotoxins; D011228:Prealbumin; D016194:Receptors, N-Methyl-D-Aspartate; D019061:src-Family Kinases