title: Deletion of Neurotrophin Signaling through the Glucocorticoid Receptor Pathway Causes Tau Neuropathology.
abstract: Glucocorticoid resistance is a risk factor for Alzheimer's disease (AD). Molecular and cellular mechanisms of glucocorticoid resistance in the brain have remained unknown and are potential therapeutic targets. Phosphorylation of glucocorticoid receptors (GR) by brain-derived neurotrophic factor (BDNF) signaling integrates both pathways for remodeling synaptic structure and plasticity. The goal of this study is to test the role of the BDNF-dependent pathway on glucocorticoid signaling in a mouse model of glucocorticoid resistance. We report that deletion of GR phosphorylation at BDNF-responding sites and downstream signaling via the MAPK-phosphatase DUSP1 triggers tau phosphorylation and dendritic spine atrophy in mouse cortex. In human cortex, DUSP1 protein expression correlates with tau phosphorylation, synaptic defects and cognitive decline in subjects diagnosed with AD. These findings provide evidence for a causal role of BDNF-dependent GR signaling in tau neuropathology and indicate that DUSP1 is a potential target for therapeutic interventions.
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, F-34000 Montpellier, France.|CNRS, UMR-5203, F-34000 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Margarita
authors.initials: M
authors.lastname: Arango-Lievano
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, F-34000 Montpellier, France.|CNRS, UMR-5203, F-34000 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Peguet
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, F-34000 Montpellier, France.|CNRS, UMR-5203, F-34000 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Matthias
authors.initials: M
authors.lastname: Catteau
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, F-34000 Montpellier, France.|CNRS, UMR-5203, F-34000 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Parmentier
authors.affiliation: Skirball Institute of biomolecular medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Synphen
authors.initials: S
authors.lastname: Wu
authors.affiliation: Skirball Institute of biomolecular medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.affiliation: Center for Dementia Research, Nathan Kline Institute, Departments of Psychiatry, Neuroscience &Physiology, New York University Langone Medical Center, Orangeburg, NY 10962, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, F-34000 Montpellier, France.|CNRS, UMR-5203, F-34000 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Freddy
authors.initials: F
authors.lastname: Jeanneteau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005938:Glucocorticoids; D009414:Nerve Growth Factors; D011965:Receptors, Glucocorticoid; D054638:Dual Specificity Phosphatase 1