title: Deficiency of GDNF Receptor GFRα1 in Alzheimer's Neurons Results in Neuronal Death.
abstract: We have recently developed aged cortical neuron cultures from autopsied human brains with Alzheimer's disease (AD). During the culturing process, we found that glutamatergic cortical neurons from the AD brain lacked a response to glial cell line-derived neurotrophic factor (GDNF), including no axonal regrowth, and were starting to undergo apoptosis. Here we showed that, in cortical neurons from age- and gender-matched cognitively normal control (NC) subjects (NC neurons), GDNF enhanced the expression of GDNF family receptor subtype α1 (GFRα1), but not the other three subtypes (GFRα2, GFRα3, and GFRα4), whereas GDNF failed to induce GFRα1 expression in cortical neurons from the AD brain (AD neurons). The exogenous introduction of GFRα1, but not of its binding partner α1-neural cell adhesion molecule, or RET into AD neurons restored the effect of GDNF on neuronal survival. Moreover, between NC and AD neurons, the AMPA receptor blocker CNQX and the NMDA receptor blocker AP-5 had opposite effects on the GFRα1 expression induced by GDNF. In NC neurons, the presence of glutamate receptors was necessary for GDNF-linked GFRα1 expression, while in AD neurons the absence of glutamate receptors was required for GFRα1 expression by GDNF stimulation. These results suggest that, in AD neurons, specific impairments of GFRα1, which may be linked to glutamatergic neurotransmission, shed light on developing potential therapeutic strategies for AD by upregulation of GFRα1 expression.
authors.affiliation: Haldeman Laboratory of Molecular and Cellular Neurobiology, and Department of Clinical Research, National Tottori Medical Center, Tottori 689-0203, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Konishi
authors.affiliation: Haldeman Laboratory of Molecular and Cellular Neurobiology, and.
authors.forename: Li-Bang
authors.initials: LB
authors.lastname: Yang
authors.affiliation: Haldeman Laboratory of Molecular and Cellular Neurobiology, and.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: Haldeman Laboratory of Molecular and Cellular Neurobiology, and.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lindholm
authors.affiliation: Section on Synaptic Development, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Bai
authors.initials: B
authors.lastname: Lu
authors.affiliation: Center for Hormone Advanced Science and Education, Roskamp Institute, Sarasota, Florida 34243, Beijing Institute for Brain Disorders, Beijing, China 100069, yshen@rfdn.org rli@rfdn.org.
authors.forename: Rena
authors.initials: R
authors.lastname: Li
authors.affiliation: Haldeman Laboratory of Molecular and Cellular Neurobiology, and Center for Advance Therapeutics Strategies for Brain Disorders, Roskamp Institute, Sarasota, Florida 34243, Department of Neurology, University of Florida College of Medicine, Gainesville, Florida 31620, and The School of Life Sciences and Medical Research Center, University of Science and Technology, Hefei, Anhui 230027 China yshen@rfdn.org rli@rfdn.org.
authors.forename: Yong
authors.initials: Y
authors.lastname: Shen
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D019006:Neural Cell Adhesion Molecules; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D051096:Proto-Oncogene Proteins c-ret
keywords: neurodegeneration; neuron